Non-Covalent Interactions in Block Copolymers …...Overall, non-covalent interactions were...

Non-Covalent Interactions in Block Copolymers Synthesized via

Living Polymerization Techniques

Brian Douglas Mather

Dissertation submitted to the Faculty of the Virginia Polytechnic Institute and State University

in partial fulfillment of the requirements for the degree of

Doctor of Philosophy in

Chemical Engineering

Timothy E. Long, Chair Garth L. Wilkes, Co-Chair

James E. McGrath Richey M. Davis

Aaron S. Goldstein

April 10, 2007 Blacksburg, Virginia

Keywords: Hydrogen bonding, Block Copolymer, Living Polymerization, Nitroxide Mediated Polymerization, Ionomers, Morphology, AFM

Copyright 2007, Brian D. Mather

Non-Covalent Interactions in Block Copolymers Synthesized via Living Polymerization Techniques

Brian Douglas Mather

Abstract

Non-covalent interactions including nucleobase hydrogen bonding and ionic

aggregation were studied in block and end-functional polymers synthesized via living

polymerization techniques such as nitroxide mediated polymerization and anionic

polymerization. Non-covalent interactions were expected to increase the effective

molecular weight of the polymeric precursors through intermolecular associations and to

induce microphase separation. The influence of non-covalent association on the

structure/property relationships of these materials were studied in terms of physical properties

(tensile, DMA, rheology) as well as morphological studies (AFM, SAXS).

Hydrogen bonding, a dynamic interaction with intermediate enthalpies (10-40 kJ/mol)

was introduced through complementary heterocyclic DNA nucleobases such as adenine,

thymine and uracil. Hydrogen bonding uracil end-functionalized polystyrenes and poly(alkyl

acrylate)s were synthesized via nitroxide mediated polymerization from novel

uracil-functionalized alkoxyamine unimolecular initiators. Terminal functionalization of

poly(alkyl acrylate)s with hydrogen bonding groups increased the melt viscosity, and as

expected, the viscosity approached that of nonfunctional analogs as temperature increased.

The effects of hydrogen bonding were also evident in thermal (DSC) analysis and 1H NMR

spectroscopic investigations, and low molar mass polystyrenes exhibited glass transition

temperatures that were consistent with a higher apparent molar mass.

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A novel difunctional alkoxyamine, DEPN2, was synthesized and utilized as an efficient

initiator in nitroxide-mediated controlled radical polymerization of triblock copolymers.

Complementary hydrogen bonding triblock copolymers containing adenine (A) and thymine

(T) nucleobase-functionalized outer blocks were synthesized. These thermoplastic

elastomeric block copolymers contained short nucleobase-containing outer blocks (Mn ~

1K-4K) and n-butyl acrylate rubber blocks of variable length (Mn ~ 14K-70K). Hydrogen

bonding interactions were observed for blends of the complementary

nucleobase-functionalized block copolymers in terms of increased specific viscosity as well

as higher scaling exponents for viscosity with solution concentration. In the solid state, the

blends exhibited evidence of a complementary A-T hard phase, which formed upon annealing,

and dynamic mechanical analysis (DMA) revealed higher softening temperatures.

Morphological development of the block copolymers was studied using SAXS and AFM

which revealed intermediate interdomain spacings and surface textures for the blends

compared to the individual precursors. Hydrogen bonding interactions enabled the

compatibilization of complementary hydrogen bonding guest molecules such as

9-octyladenine.

Ionic interactions, which possess stronger interaction energies than hydrogen bonds

(~150 kJ/mol) were studied in the context of sulfonated

poly(styrene-b-ethylene-co-propylene-b-styrene) block copolymers. As for hydrogen bonding

block copolymers, only short block molecular weights of the sulfonated blocks (1K) were

necessary to achieve microphase separation. Strong ionic interactions resulted in the

development of a microphase separated physical network and greater extents for the rubbery

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plateau in DMA analysis compared to sulfonic acid groups, which exhibit weak hydrogen

bonnding interactions. Small-angle X-ray scattering revealed trends in terms of inter-domain

spacing as a function of center block molecular weight.

Multiple hydrogen bonding interactions were utilized to reversibly attach

nucleobase-functional quaternary phosphonium ionic guests to complementary

adenine-functionalized triblock copolymers. The ionic guest molecules formed optically clear

blends with the adenine-functional block copolymer. The presence of the ionic groups

resulted in screening of interchain hydrogen bonding interactions, leading to lower solution

viscosity and lower softening temperatures for the hard phases. The incorporation of the

phosphonium salt guest molecules induced a transition from a cylindrical to lamellar

morphology due to increased volume fraction of the hard phase. The molecular recognition

between a water-soluble uracil-functionalized phosphonium salt and an adenine-containing

block copolymer surface was observed using quartz crystal microbalance with dissipation

(QCM-D) measurements

In contrast to the physical networks consisting of sulfonated or hydrogen bonding block

copolymers, covalent networks were synthesized using carbon-Michael addition chemistry of

acetoacetate functionalized telechelic oligomers to diacrylate Michael acceptors. The

thermomechanical properties of the networks based on poly(propylene glycol) oligomers

were analyzed with respect to the molecular weight between crosslink points (Mc) and the

critical molecular weight for entanglement (Me). Kinetic analyses of the Michael additions

were performed using 1H NMR spectroscopy, and the influence of basic catalyst and

concentration were elucidated. A novel acid-cleavable diacrylate crosslinker, dicumyl alcohol

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diacrylate (DCDA), was synthesized. DCDA was utilized as a difunctional Michael acceptor

in the synthesis of acid-cleavable crosslinked networks via base-catalyzed Michael addition

of telechelic poly(ethylene glycol) bis(acetoacetate).

Overall, non-covalent interactions were introduced into block and end-functionalized

polymers, resulting in associations between polymer chains and the formation of physical

networks in the case of functional block copolymers. Effects of these non-covalent

interactions on a number of physical properties were investigated. Covalent networks

composed were also synthesized via Michael addition chemistry and the effect of precursor

chain length was investigated.

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Acknowledgements

First, I would like to thank my advisor, Prof. Timothy E. Long, for his guidance and

inspiration over the course of my graduate carreer. Your wealth of ideas and contageous

enthusiasm has never ceased to amaze me. It has been a pleasure working with you and I

have learned a great deal. I am grateful for the summer research internship in 2000, which

ultimately led me back to your group for graduate school. I also would like to thank my

co-advisor, Prof. Garth L. Wilkes, who was always willing to share his wisdom and technical

expertise. You have been a great co-advisor and important bridge to the Chemical

Engineering department. Prof. James E. McGrath, Prof. Richey M. Davis and Prof. Aaron S.

Goldstein have also been insightful and helpful committee members and teachers during my

graduate career. I would also like to thank Prof. S. Richard Turner for his helpful discussions

and his very practical class on the transition to industry. I would like to thank Prof. Judy S.

Riffle, for being a great teacher in both presentation skills and polymer synthesis courses.

I would like to thank Laurie Good and Millie Ryan who have truly been lifesavers.

They have always been willing to help and have also been good friends. I would like to

thank Vicki Long, who has helped me many times in both technical work and organizing

travel. Also, I would like to thank Tammy Jo Hiner, who has been instrumental during the

interviewing process. I would like to also thank Angie Flynn, who is one of the primary

organizers of the SURP program that brought me to VT.

I would like to thank the Macromolecular Architecture for Performance

Multidisciplinary University Research Initiative (MAP MURI), which has provided funding

for my research over the last several years. The MURI grant has also facilitated many

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positive interactions with students and faculty in other universities (such as Prof. Ralph Colby

at Penn State University and Prof. Geoff Coates at Cornell University). Dr. Cheryl Heisey,

Rebecca Heath and Mary Dean Coleman served as organizers of the MAP MURI research

program. I am thankful to Cheryl for editing my papers.

I would also like to thank Kraton Polymers and Rohm and Haas for supporting my

research both financially and through collaborations. I would like to thank Dr. Carl Willis

and Dr. Dale Handlin from Kraton Polymers for their insightful discussions. I would also

like to thank Dr. Kevin Miller and Thomas Kauffman from Rohm and Haas, who

collaborated with us through a grant from the Department of Energy.

I would also like to thank Dr. Carl Willis, Dr. Peter Pasman, Dr. Dale Handlin and Dan

Goodwin with whom I spent an exciting summer at Kraton Polymers in Houston, TX in 2004.

The internship was an excellent opportunity to learn about the industrial side of polymer

research and has recently led to a patent application and a successful product launch.

I would like to thank Dr. Rick Beyer at the Army Research Laboratories in Aberdeen,

MD who has been an excellent collaborator and has always been willing to share his

expertise in X-ray scattering analysis of polymers. I enjoyed spending two weeks in Aberdeen

with him learning about X-ray scattering and our collaboration has been fruitful.

The staff at Virginia Tech have been a great resource. I would especially like to

acknowledge Steve McCartney for his help with microscopy, and Mark Flynn for his help

with SEC analysis. Tom Glass, Geno Iannaconne and Bill Bebout have also been a great help.

Michael Berg and Carla Slebodnick have been great resources for single crystal X-ray

diffraction. Jan McGinty has been a great resource for helping our research group to function

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properly and keeping the stockroom working.

I would like to thank Prof. Hiroyuki Nishide and his student, Dr. Takeo Suga from

Waseda University in Tokyo, Japan, with whom I have collaborated in the last year. They

were excellent hosts during my two-week visit to Waseda in November of 2006.

I would also like to thank those that I worked with during undergraduate research. My

first research experience was with Prof. James A. Brozik at the University of New Mexico.

Dr. Douglas Loy taught my first class on polymers and hired me as a student intern at Sandia

National Laboratories where I met Dr. Christopher Cornelius.

I would especially like to thank my research group including post-docs and

undergraduates, whom I have enjoyed interacting with. You have been good friends and I

have enjoyed the good times working together. Tomonori, Sharlene, Gozde, Serkan, Casey,

Dave, Afia, Lars, Qin and Emily made the upstairs labs enjoyable. I valued the mentorship

from Dave and Jeremy. Ann, Matt M., Matt G., Matt H., Matthew, Erika, Rebecca, Bill and

Funda were also fun people to interact with. I would also like to thank Margaux Baker, a

dedicated summer undergraduate student that I worked with from the University of Michigan.

My greatest appreciation and deepest thanks goes to my wife, Qian, who I was blessed

to have met in graduate school. You have been my greatest inspiration and my constant

companion during graduate school, providing me with great support. With your love, I

believe I can achieve anything. I look forward to our life together in San Diego after

graduation. I have to appreciate “Poly and the Mers” for the music and Halloween party that

brought us together.

Finally, I would like to thank my parents, Doug Mather and Joan Voute, who supported

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me throughout graduate school with their words of encouragement, numerous visits and

occasional box of pomegranates. I have enjoyed your visits to B’burg, including floating

down the New River, hiking up Dragon’s tooth, or taking a dip in the Cascades. Thanks for

helping to keep me sane through all of this. I would like to thank my wife’s parents, Yunling

Jiang and Baiyuan Zhang, who took great care of us during our stay in China. Last, but not

least, I would like to thank my “little” brother, Joe and his wife Cheri. You two are a lovely

couple, and I look forward to seeing the kids soon…

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Attribution

Several colleagues and coworkers aided in the writing and research behind several of

the chapters of this dissertation. A brief description of their background and their

contributions are included here.

Prof. Timothy E. Long- Ph.D. (Department of Chemistry, Virginia Tech) is the primary

Advisor and Committee Chair. Prof. Long provided the research direction for all work during

the author’s graduate study. Furthermore, Prof. Long also directed the composition of the

chapters, extensively edited each chapter in this dissertation and is the corresponding author

of all papers published.

Chapter 3: Michael Addition Reactions in Macromolecular Design for Emerging

Technologies

Kalpana Viswanathan- Ph.D. (Department of Chemistry, Virginia Tech) currently at Guidant

Corporation was a student in the author’s group and contributed during her graduate studies

to this chapter in terms of discussing the applications of the Michael addition reaction in

sections 3.7 and 3.8.

Kevin M. Miller- Ph.D. (Department of Chemistry, University of Notre Dame) is employed

by Rohm and Haas Company and worked in collaboration with the author on a project

supported from Department of Energy. Kevin contributed to the discussion of the

mechanism of the Michael addition reaction in sections 3.3.1 and 3.3.2.

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Chapter 4: Synthesis of Chain End Functionalized Multiple Hydrogen Bonded Polystyrenes

and Poly(alkyl acrylates) via Nitroxide Mediated Radical Polymerization

Jeremy R. Lizotte- Ph.D. (Department of Chemistry, Virginia Tech) currently at Eastman

Chemical Company, was a member of the author’s research group. His mentorship aided in

the publication of this chapter and he contributed through helpful discussions.

Chapters 5 and 6: Supramolecular Triblock Copolymers Containing Complementary

Nucleobase Molecular Recognition and Multiple Hydrogen Bonding for the Non-covalent

Attachment of Ionic Functionality in Block Copolymers

Margaux B. Baker- Undergraduate student (Department of Chemical Engineering,

University of Michigan) was a summer undergraduate intern who aided in the experimental

work for this chapter, in particularly in the synthesis of nucleobase functional block

copolymers.

Frederick L. Beyer- Ph.D. (Polymer Science and Engineering, University of Massachusetts

in Amherst) is a researcher at the Army Research Laboratory in Abderdeen, MD. Rick

contributed to this work by carrying out extensive SAXS analysis and through editing the

chapters.

Matthew D. Green- Undergraduate student (Department of Chemical Engineering, Virginia

Tech) is an undergraduate researcher in the author’s group and aided in solution rheological

experiments described in this chapter.

Michael A.G. Berg- Ph.D. (Department of Chemistry, Virginia Tech) is an instructor at the

Department of Chemistry at Virginia Tech. He contributed by obtaining X-ray

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crystallographic structures for the compounds in these chapters.

Chapter 7: Novel Michael Addition Networks Containing Poly(propylene glycol) Telechelic

Oligomers

Kevin M. Miller- Ph.D. contributed by synthesizing the bisAcAc terminated poly(propylene

glycol)s which were further reacted in this study to form networks.

Chapter 8: Synthesis of an Acid-Labile Diacrylate Crosslinker for Cleavable Michael

Addition Networks

Sharlene R. Williams- Graduate Student (Department of Chemistry, Virginia Tech) is a

member of the author’s research group and contributed through the synthesis of the bisAcAc

terminated poly(ethylene glycol)

Chapter 9: Synthesis and Morphological Characterization of Sulfonated Triblock

Copolymers: Influence of High Sulfonate Levels and Poly(ethylene-co-propylene) Molecular

Weight

Frederick L. Beyer- Ph.D. contributed through teaching the author how to carry out SAXS

analysis of the sulfonated block copolymers. Rick contributed further through scientific

discussions and through editing the chapter.

Dale L. Handlin- Ph.D. (Polymer Science and Engineering, University of Massachusetts in

Amherst) is a researcher at Kraton Polymers. Dale contributed to this chapter through

scientific discussions as well as introducing a model for analyzing the tensile behavior of the

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polymers studied.

Chapter 10: Morphological Analysis of Telechelic Ureido-Pyrimidone Functional Hydrogen

Bonding Linear and Star-Shaped Poly(ethylene-co-propylene)s

Casey L. Elkins- Ph.D. (Department of Chemistry, Virginia Tech) was a member of the

author’s research group and is currently employed by DuPont Company. Casey carried out

the synthesis of the UPy terminated polymers and published a paper on these prior to the

studies that resulted in this chapter. Casey also contributed through editing this chapter and

scientific discussions.

Frederick L. Beyer- Ph.D. contributed through teaching the author how to carry out SAXS

analysis of the UPy terminated copolymers. Rick contributed further through numerous

helpful discussions and editing the chapter.

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Table of Contents

CHAPTER 1. INTRODUCTION........................................................................................................................ 1

1.1 SCIENTIFIC RATIONALE AND PERSPECTIVE ................................................................................................. 1

CHAPTER 2. REVIEW OF THE LITERATURE – HYDROGEN BOND FUNCTIONALIZED BLOCK COPOLYMERS AND TELECHELIC HYDROGEN BONDING OLIGOMERS ......................................... 5

2.1 FUNDAMENTALS OF HYDROGEN BONDING.................................................................................................... 5 2.2 PERFORMANCE ADVANTAGES OF HYDROGEN BONDING POLYMERS ....................................................... 11 2.3 HYDROGEN BONDING BLOCK COPOLYMERS ............................................................................................... 20

2.3.1 Block Copolymers Involving Single Hydrogen Bonding Groups......................................................... 22 2.3.2 Nucleobase Containing Hydrogen Bonding Block Copolymers .......................................................... 28 2.3.3 Block Copolymers Containing DNA Oligonucleotides........................................................................ 37 2.3.4 Block Copolymers Containing other Hydrogen Bonding Arrays ........................................................ 40 2.3.5 Order-Disorder Transitions (ODT) in Hydrogen Bonding Block Copolymers .................................... 42

2.4 TELECHELIC HYDROGEN BOND FUNCTIONAL POLYMERS............................................................................ 43 2.5 COMBINING HYDROGEN BONDING WITH OTHER NON-COVALENT INTERACTIONS....................................... 55 2.6 REVERSIBLE ATTACHMENT OF GUEST MOLECULES VIA HYDROGEN BONDING............................................ 57 2.7 CONCLUSIONS AND SUMMARY................................................................................................................... 63

CHAPTER 3. REVIEW OF THE LITERATURE – MICHAEL ADDITION REACTIONS IN MACROMOLECULAR DESIGN FOR EMERGING TECHNOLOGIES .................................................. 65

3.1 ABSTRACT .................................................................................................................................................. 65 3.2 MOTIVATION AND SCIENTIFIC RATIONALE............................................................................................... 65 3.3. INTRODUCTION TO THE MICHAEL ADDITION REACTION ........................................................................ 70

3.3.1 Mechanism of the Carbon-Michael Addition Reaction..................................................................... 70 3.3.1.1 Effect of Base Strength.................................................................................................................................75 3.3.1.2 Effect of Solvent ...........................................................................................................................................76 3.3.1.3 Effect of Substrate........................................................................................................................................77 3.3.1.4 Other Carbon-Michael Catalysts ................................................................................................................80

3.3.2 Heteroatomic Donors in the Michael Addition Reaction .................................................................. 85 3.3.2.1. The aza-Michael Reaction ..........................................................................................................................85 3.3.2.2. Thiols as Michael Donors ...........................................................................................................................95

3.4 LINEAR STEP GROWTH MICHAEL ADDITION POLYMERIZATIONS ........................................................... 98 3.4.1 Overview ............................................................................................................................................. 98 3.4.2 Poly(amido amine)s .......................................................................................................................... 101 3.4.3 Poly(imido sulfide)s ...........................................................................................................................111 3.4.4 Poly(aspartamide)s ........................................................................................................................... 117 3.4.5 Poly(amino quinone)s ...................................................................................................................... 123 3.4.6 Step Growth Polymers Derived from Bisacetylene-Containing Monomers.................................... 127 3.4.7 Hydrogen transfer polymerization ................................................................................................... 128

3.5 LINEAR CHAIN GROWTH MICHAEL ADDITION POLYMERIZATIONS ...................................................... 133

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3.5.1. Anionic Polymerization of Methacrylates....................................................................................... 134 3.5.2 Group Transfer Polymerization ....................................................................................................... 141 3.5.3 Anionic Polymerization of α-cyanoacrylates................................................................................... 143 3.5.4 Living Radical Polymerization ......................................................................................................... 145

3.6 SYNTHESIS OF BRANCHED POLYMERS VIA THE MICHAEL ADDITION REACTION.................................. 148 3.6.1 Dendrimers ....................................................................................................................................... 149 3.6.2 Hyperbranched and Highly Branched Polymers ............................................................................ 159 3.6.3 Graft Copolymers.............................................................................................................................. 172

3.7 NOVEL NETWORKS VIA THE MICHAEL ADDITION REACTION................................................................ 177 3.7.1 Bismaleimide Networks and Composite Materials .......................................................................... 177 3.7.2 Carbon Michael Addition Networks Utilizing Acetoacetate Chemistry .......................................... 180 3.7.3 Curing Mechanisms Involving Michael Addition with Photocrosslinking or Sol-Gel Chemistry . 185 3.7.4 Hydrogel Networks for Biomedical Applications ............................................................................ 190

3.8 BIOCONJUGATES VIA THE MICHAEL ADDITION REACTION.................................................................... 207 3.8.1 Polymer-Protein and Polymer-Drug Conjugates............................................................................. 207 3.8.2 Coupling of Biological Molecules to Michael Addition Polymers .................................................. 216

3.9 CONCLUSIONS AND FUTURE DIRECTIONS ............................................................................................... 217 3.10 ACKNOWLEDGEMENTS .......................................................................................................................... 218

CHAPTER 4. SYNTHESIS OF CHAIN END FUNCTIONALIZED MULTIPLE HYDROGEN BONDED POLYSTYRENES AND POLY(ALKYL ACRYLATES) VIA NITROXIDE MEDIATED RADICAL POLYMERIZATION ....................................................................................................................................... 219

4.1 ABSTRACT ................................................................................................................................................ 219 4.2 INTRODUCTION ........................................................................................................................................ 220 4.3 EXPERIMENTAL ........................................................................................................................................ 226

4.3.1 Materials ........................................................................................................................................... 226 4.3.2 Synthesis of Uracil-TEMPO Unimolecular Initiator ...................................................................... 226 4.3.3 Synthesis of Uracil-DEPN Unimolecular Initiator ......................................................................... 227 4.3.4 Polymerizations of Styrene Using Uracil-TEMPO .......................................................................... 228 4.3.5 Polymerizations of n-Butyl Acrylate Using Uracil-DEPN .............................................................. 229 4.3.6 Polymer Characterization................................................................................................................. 230

4.4 RESULTS AND DISCUSSION ....................................................................................................................... 231 4.4.1 Uracil-TEMPO and Uracil-DEPN Unimolecular Initiator Syntheses ........................................... 231 4.4.2 Polymerizations of Styrene and n-Butyl Acrylate Using the Uracil Based Initiators ..................... 234 4.4.3 In-situ FTIR Monitoring of Polymerization Kinetics ..................................................................... 238 4.4.4 Characterization of Hydrogen Bonding Using 1H NMR Spectroscopy .......................................... 244 4.4.5 Characterization of Hydrogen Bonding Using Melt Rheology ....................................................... 247 4.4.6 Thermal Analysis of Uracil Polystyrenes ......................................................................................... 251

4.5 CONCLUSION ............................................................................................................................................ 255 4.6 ACKNOWLEDGEMENT .............................................................................................................................. 255

CHAPTER 5. SUPRAMOLECULAR TRIBLOCK COPOLYMERS CONTAINING COMPLEMENTARY NUCLEOBASE MOLECULAR RECOGNITION................................................. 256

5.1 ABSTRACT ................................................................................................................................................ 256 5.2 INTRODUCTION ........................................................................................................................................ 257

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5.3 EXPERIMENTAL ........................................................................................................................................ 265 5.3.1 Materials ........................................................................................................................................... 265 5.3.2 Synthesis of DEPN2 .......................................................................................................................... 265 5.3.3 Polymerization of n-Butyl Acrylate with DEPN2............................................................................. 267 5.3.4 Synthesis of Thymine-Containing Block Copolymer ...................................................................... 267 5.3.5 Synthesis of Adenine-Containing Block Copolymer ....................................................................... 268 5.3.6 Blends of Adenine and Thymine Functionalized Block Copolymers and Sample Preparation..... 269 5.3.7 Polymer Characterization................................................................................................................. 270

5.4 RESULTS AND DISCUSSION ....................................................................................................................... 272 5.4.1 Synthesis of a Novel Difunctional Alkoxyamine Initiator .............................................................. 272 5.4.2 Performance of DEPN2 in the Homopolymerization of n-Butyl Acrylate ...................................... 274 5.4.3 Synthesis of Nucleobase-Functionalized Hydrogen Bonding Block Copolymers.......................... 279 5.4.4 Complementary Hydrogen Bonding Interactions in Solution and Solid State ............................... 282 5.4.5 Morphological Investigations of Nucleobase-Functionalized Block Copolymers and Blends ...... 292 5.4.6 Introduction of Guest Molecules to Hydrogen Bonding Block Copolymers .................................. 305

5.5 CONCLUSIONS .......................................................................................................................................... 310 5.6 ACKNOWLEDGEMENT .............................................................................................................................. 310

CHAPTER 6. MULTIPLE HYDROGEN BONDING FOR THE NON-COVALENT ATTACHMENT OF IONIC FUNCTIONALITY IN BLOCK COPOLYMERS............................................................................ 311


6.3.1 Materials ........................................................................................................................................... 317 6.3.2 Synthesis of 6-(trioctylphosphonium methyl)uracil chloride (UP+)................................................ 317 6.3.3 Synthesis of DEPN2 Difunctional Alkoxyamine Initiator ............................................................... 318 6.3.4 Polymerization of n-Butyl Acrylate from DEPN2 Nitroxide............................................................ 320 6.3.5 Synthesis of Adenine Containing Block Copolymer........................................................................ 320 6.3.6 Characterization ............................................................................................................................... 321

6.4 RESULTS AND DISCUSSION ....................................................................................................................... 322 6.4.1 Synthesis and Characterization of a Novel Difunctional Initiator ................................................. 322 6.4.2 Synthesis of Adenine Functional Block Copolymer........................................................................ 326 6.4.3 Compatible Blends of Adenine Functional Block Copolymer with Uracil Phosphonium Salt...... 328 6.4.4 Morphological Characterization of Phosphonium Salt Blends ...................................................... 330 6.4.5 Effect of Phosphonium Salt on Solution and Solid State Properties .............................................. 334

6.5 CONCLUSION ............................................................................................................................................ 336 6.6 ACKNOWLEDGMENT ................................................................................................................................ 336

CHAPTER 7. NOVEL MICHAEL ADDITION NETWORKS CONTAINING POLY(PROPYLENE GLYCOL) TELECHELIC OLIGOMERS..................................................................................................... 337


7.3.1 Materials ........................................................................................................................................... 343 7.3.2 Synthesis of Acetoacetate Functionalized Poly(propylene glycol) (PPG bisAcAc) ........................ 344

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7.3.3 Crosslinking Reactions..................................................................................................................... 345 7.3.4 SEC and 1H NMR Analysis of the Crosslinking Process................................................................. 345 7.3.5 1H NMR Kinetics Experiments ........................................................................................................ 345 7.3.6 Polymer Characterization................................................................................................................. 346

7.4 RESULTS AND DISCUSSION ....................................................................................................................... 347 7.4.1 Synthesis of Acetoacetate Functionalized Poly(propylene glycol) (PPG bisAcAc) ........................ 347 7.4.2 Synthesis of carbon-Michael Addition Networks ............................................................................ 348 7.4.3 Characterization of the PPG bisAcAc / PEG diacrylate Networks ................................................. 351 7.4.4 Sampling Experiments of the Crosslinking Reaction Involving SEC Analysis.............................. 363 7.4.5 Kinetic Investigations of the carbon-Michael Addition Crosslinking Reaction ............................. 367

7.5 CONCLUSIONS .......................................................................................................................................... 371 7.6 ACKNOWLEDGEMENTS ............................................................................................................................ 371

CHAPTER 8. SYNTHESIS OF AN ACID-LABILE DIACRYLATE CROSSLINKER FOR CLEAVABLE MICHAEL ADDITION NETWORKS ........................................................................................................... 372


8.3.1 Materials ........................................................................................................................................... 377 8.3.2 Dicumyl alcohol diacrylate (DCDA) ................................................................................................ 377 8.3.3 Poly(ethylene glycol) bis(acetoacetate) ............................................................................................ 378 8.3.4 Crosslinked Network Synthesis and Degradation ........................................................................... 378 8.3.5 Characterization ............................................................................................................................... 379

8.4 RESULTS AND DISCUSSION ....................................................................................................................... 380 8.4.1 Synthesis of Acid-Cleavable Networks............................................................................................. 380 8.4.2 Acid Catalyzed Degradation of Networks ........................................................................................ 383 8.4.3 Thermal Degradation of Networks .................................................................................................. 386 8.4.4 Mechanical Characterization of Networks ...................................................................................... 388

8.5 CONCLUSION ............................................................................................................................................ 392 8.6 ACKNOWLEDGEMENT .............................................................................................................................. 392

CHAPTER 9. SYNTHESIS AND MORPHOLOGICAL CHARACTERIZATION OF SULFONATED TRIBLOCK COPOLYMERS: INFLUENCE OF HIGH SULFONATE LEVELS AND POLY(ETHYLENE-CO-PROPYLENE) MOLECULAR WEIGHT........................................................... 393


9.3.1 Materials ........................................................................................................................................... 399 9.3.2 Synthesis of Poly(styrene-b-isoprene-b-styrene) Triblock Copolymers........................................... 400 9.3.3 Hydrogenation of Poly(styrene-b-isoprene-b-styrene) Triblock Copolymers.................................. 401 9.3.4 Sulfonation of Poly(styrene-b-ethylene-co-propylene-b-styrene) Triblock Copolymers ................ 402 9.3.5 Titration and Neutralization of Sulfonated Poly(styrene-b-ethylene-co-propylene-b-styrene) ...... 402 9.3.6 Small Angle X-Ray Scattering (SAXS) Measurements ................................................................... 403 9.3.7 Atomic Force Microscopy (AFM) Measurements ........................................................................... 404 9.3.8 Size Exclusion Chromatography...................................................................................................... 404

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9.3.9 Dynamic Mechanical Analysis, Thermal and Rheological Studies ................................................ 404 9.4 RESULTS AND DISCUSSION ....................................................................................................................... 405

9.4.1 Sulfonated SEPS Triblock Polymer Synthesis................................................................................. 405 9.4.2 Dynamic Mechanical Analysis (DMA) of Sulfonated SEPS Triblock Polymers............................ 410 9.4.3 Tensile Characterization of Sulfonated SEPS Polymers................................................................. 415 9.4.4 Rheological Studies of Sulfonated Block Copolymers .................................................................... 422 9.4.5 Small Angle X-Ray Scattering Characterization ............................................................................. 425 9.4.6 Atomic Force Microscopy (AFM) Characterization........................................................................ 431

9.5 CONCLUSIONS .......................................................................................................................................... 434 9.6 ACKNOWLEDGEMENTS ............................................................................................................................ 434

CHAPTER 10. MORPHOLOGICAL ANALYSIS OF TELECHELIC UREIDO-PYRIMIDONE FUNCTIONAL HYDROGEN BONDING LINEAR AND STAR-SHAPED POLY(ETHYLENE-CO-PROPYLENE)S...................................................................................................... 435

10.1 ABSTRACT .............................................................................................................................................. 435 10.2 INTRODUCTION ...................................................................................................................................... 436 10.3 EXPERIMENTAL ...................................................................................................................................... 444

10.3.1 Materials ......................................................................................................................................... 444 10.3.2 Polymer Characterization............................................................................................................... 444 10.3.3 Small-angle X-ray Scattering (SAXS) Measurements................................................................... 445 10.3.4 Atomic Force Microscopy (AFM) Measurements ......................................................................... 446

10.4 RESULTS AND DISCUSSION ..................................................................................................................... 446 10.4.1 Polymer Synthesis........................................................................................................................... 446 10.4.2 Small-angle X-Ray Scattering Studies ........................................................................................... 450 10.4.3 Atomic Force Microscopy............................................................................................................... 458

10.5 CONCLUSIONS ........................................................................................................................................ 461 10.6 ACKNOWLEDGEMENTS .......................................................................................................................... 461

CHAPTER 11. REAL-TIME MONITORING OF MOLECULAR RECOGNITION OF COMPLEMENTARY IONIC GUEST MOLECULES WITH HYDROGEN BONDING BLOCK COPOLYMERS USING QUARTZ-CRYSTAL MICROBALANCE WITH DISSIPATION (QCM-D)... 462

11.1 ABSTRACT............................................................................................................................................... 462 11.2 INTRODUCTION....................................................................................................................................... 463 11.3 EXPERIMENTAL........................................................................................................................................ 468

11.3.1 Materials ......................................................................................................................................... 468 11.3.2 Polymerization of n-Butyl Acrylate from DEPN2 .......................................................................... 468 11.3.3 Synthesis of Adenine Containing Block Copolymer ...................................................................... 469 11.3.4 Synthesis of Poly(styrene-b-n-butyl acrylate-b-styrene) Block Copolymer................................... 469 11.3.5 Characterization ............................................................................................................................. 470 11.3.6 Quartz Crystal Microbalance with Dissipation (QCM-D) Measurements .................................... 471

11.4 RESULTS AND DISCUSSION ..................................................................................................................... 471 11.4.1 Synthesis of Nucleobase Functional Hydrogen Bonding Block Copolymers............................... 471 11.4.2 Quartz Crystal Microbalance Measurements................................................................................. 474 11.4.3 X-ray Crystallographic Studies of Uracil Phosphonium Salt........................................................ 484

11.5 CONCLUSIONS ........................................................................................................................................ 488

xix

11.6 ACKNOWLEDGEMENT ............................................................................................................................ 488

CHAPTER 12. INTRODUCTION OF CENTRAL DIESTER FUNCTIONALITY IN POLYSTYRENES USING LIVING RADICAL POLYMERIZATION FOR GRAFT POLYESTER SYNTHESIS............... 489

12.1 ABSTRACT .............................................................................................................................................. 489 12.2 INTRODUCTION ...................................................................................................................................... 489 12.3 EXPERIMENTAL ...................................................................................................................................... 494

12.3.1 Materials ......................................................................................................................................... 494 12.3.2 Polystyrene Diester Synthesis......................................................................................................... 494 12.3.3 Removal of DEPN from Polystyrene Diester ................................................................................. 495 12.3.4 Graft Polyester Synthesis................................................................................................................ 495 12.3.5 Characterization ............................................................................................................................. 497

12.4 RESULTS AND DISCUSSION ..................................................................................................................... 498 12.4.1 Synthesis of DEPN-Terminated Polystyrene Diesters ................................................................... 498 12.4.2 Removal of DEPN End-groups from Polystrene Diesters............................................................. 501 12.4.3 Synthesis of Graft Copolymers....................................................................................................... 506

12.5 CONCLUSION .......................................................................................................................................... 512 12.6 ACKNOWLEDGEMENT ............................................................................................................................ 512

CHAPTER 13. FUTURE DIRECTIONS - INTRODUCTION OF CHIRAL HYDROGEN BONDING GUEST MOLECULES FOR INFLUENCE OF TACTICITY OF RADICAL POLYMERIZATIONS ... 513

13.1 ABSTRACT .............................................................................................................................................. 513 13.2 INTRODUCTION ...................................................................................................................................... 513 13.3 EXPERIMENTAL ....................................................................................................................................... 519

13.3.1 Materials ......................................................................................................................................... 519 13.3.2 Synthesis of 2’,3’,5’-trihexyladenosine (AdHex)........................................................................... 519 13.3.3 Synthesis of 1-(2-bromoethyl)thymine ........................................................................................... 520 13.3.4 Synthesis of 1-vinylthymine............................................................................................................ 520 13.3.5 Free radical polymerization of 1-vinylthymine.............................................................................. 521 13.3.6 Polymerization of 1-vinylthymine in the Presence of a Chiral Auxiliary ..................................... 522 13.3.7 Free radical polymerization of 1-vinylbenzylthymine ................................................................... 522 13.3.8 Polymerization of 1-vinylbenzylthymine in the Presence of a Chiral Auxiliary........................... 522 13.3.9 Characterization ............................................................................................................................. 523

13.4 RESULTS AND DISCUSSION ..................................................................................................................... 523 13.5 CONCLUSIONS ........................................................................................................................................ 534 13.6 FUTURE WORK....................................................................................................................................... 534 13.7 ACKNOWLEDGEMENT ............................................................................................................................ 534

CHAPTER 14. FUTURE DIRECTIONS- RHEOLOGICAL STUDIES OF HYDROGEN BONDING COPOLYMERS WITH REVERSIBLE ATTACHMENT OF IONIC FUNCTIONALITY ...................... 535

14.1 ABSTRACT .............................................................................................................................................. 535 14.2 INTRODUCTION ...................................................................................................................................... 536 14.3 EXPERIMENTAL ....................................................................................................................................... 542

14.3.1 Materials ......................................................................................................................................... 542 14.3.2 Phosphonium Styrene Monomer Synthesis ................................................................................... 542

xx

14.3.3 Uracil Phosphonium Salt ............................................................................................................... 543 14.3.4 Adenine Containing Copolymer ..................................................................................................... 543 14.3.5 Phosphonium Salt Containing Copolymer .................................................................................... 544 14.3.6 Blends of an Adenine Containing Copolymer with a Uracil Phosphonium Salt.......................... 545 14.3.7 Characterization ............................................................................................................................. 545

14.4 RESULTS AND DISCUSSION ..................................................................................................................... 546 14.5 CONCLUSIONS ........................................................................................................................................ 561 14.6 FUTURE WORK ....................................................................................................................................... 561 14.7 ACKNOWLEDGEMENT ............................................................................................................................ 561

CHAPTER 15. OVERALL CONCLUSIONS ................................................................................................ 563

VITAE................................................................................................................................................................ 566

xxi

List of Tables

Table 3.1. Step growth polymers derived from Michael addition polymerization. ........100 Table 4.1. Target and experimental molecular weights for polystyrenes and poly(n-butyl

acrylate)s synthesized using Uracil-TEMPO and Uracil-DEPN. ...........................236 Table 4.2. Uracil functionalized polystyrene and poly(n-butyl acrylate) molecular weights

determined using both GPC and NMR. ..................................................................237 Table 4.3. Polymerization rate constants for various styrene to Uracil-TEMPO ratios. 241 Table 4.4 Glass transition temperatures for various uracil functionalized polystyrenes with

molecular weights below the critical molecular weight. ........................................254 Table 5.1. Molecular weight data for nucleobase-functionalized block copolymers and

blends. .....................................................................................................................281 Table 5.2. Small-angle X-ray scattering results for hydrogen bonding block copolymers.

.................................................................................................................................301 Table 7.1. Characterization of PPG bisAcAc precursors. ...............................................349 Table 7.2. Gel fractions for PPG bisAcAc / PEG diacrylate networks...........................353 Table 7.3. Tensile properties of PPG-bisAcAc/ PEG diacrylate networks. ....................359 Table 7.4. Swelling properties of PPG bisAcAc / PEG diacrylate networks in ethanol and

Mc values calculated from both swelling and tensile data. .....................................362 Table 7.5. Kinetic data for the PPG bisAcAc / PEG diacrylate reaction using various basic

catalysts. The pKa data is in aqueous solution. ......................................................370 Table 9.1. Compositional analysis of block copolymers. ...............................................409 Table 9.2. Tensile properties of sulfonated SEPS block copolymers and fitting parameters

using model from van der Heide.............................................................................417 Table 9.3. Summary of scattering maxima position and Bragg spacing for sulfonated block

copolymers..............................................................................................................428 Table 10.1. Molecular weight and molecular weight distribution of monofunctional,

telechelic, and star-shaped polyisoprenes before and after hydrogenation and UPy functionalization. ....................................................................................................448

Table 10.2. Scattering maxima and corresponding Bragg spacings for UPy functional poly(ethylene-co-propylene)s. ................................................................................454

Table 11.1. Film thickness of adenine containing polymer using QCM and SEM.........475 Table 11.2. Effect of moisture uptake on frequency and dissipation of adenine containing

polymer and control polymer. .................................................................................479 Table 11.3. Adsorption of UPPh3

+ on adenine-containing and control block copolymers..................................................................................................................................483

Table 12.1. Molecular weight characterization of polystyrene diesters..........................500 Table 14.1. Yarusso-Cooper fitting of scattering for 30 mol% phosphonium copolymer.

.................................................................................................................................554

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List of Figures

Figure 2.1. Degree of non-covalent polymerization as a function of association constant

(Ka) .........................................................................................................................13 Figure 2.2. An Archimedean tile morphology for blends of

poly(2-vinylpyridine-b-isoprene-b-vinylpyridine) with poly(styrene-b-4-hydroxystyrene) ............................................................................25

Figure 2.3. Synthesis of adenine containing block copolymers via a ROMP methodology...................................................................................................................................32

Figure 2.4. Formation of cylindrical aggregates via multi-directional self-association bonding of adenine functional block copolymers. ....................................................33

Figure 2.5. Scheme for stepwise synthesis of oligonucleotides via coupling of phosphoramidite functionalized nucleosides. ...........................................................38

Figure 2.6. Solution viscosity of (a) telechelic UPy functional PDMS and (b) benzyl protected analog in chloroform at 20 oC...................................................................46

Figure 2.7. UPy homodimer (left) and heterodimer (right) with Napy via tautomerization...................................................................................................................................50

Figure 2.8. Association of ditopic self-complementary tetraurea functional calixarenes. 54 Figure 2.9. Dual side chain non-covalent interaction modes including both hydrogen

bonding and metal-ligand interactions......................................................................56 Figure 2.10. Phase diagram of poly(isoprene-b-2-vinylpyridine) with octyl gallate........61 Figure 3.1 a) Arthur Michael (1855-1942), who discovered the Michael addition reaction.

...................................................................................................................................69 Figure 3.2. General carbon-Michael reaction mechanistic scheme. .................................72 Figure 3.3. Second Michael addition of acetoacetate group to methyl acrylate.............74 Figure 3.4. Michael Addition involving an alkyne acceptor.............................................79 Figure 3.5. Lewis-acid catalyzed Michael addition reaction..........................................82 Figure 3.6. Stereoselective Michael addition between enone and silyl enolate in the

presence of TiCl4.......................................................................................................83 Figure 3.7. Phosphine catalyzed Michael addition reaction. ............................................84 Figure 3.8. Aza-Michael addition reaction of dimethylamine with ethyl acrylate. ..........86 Figure 3.9. Aza-Michael addition of methyl amine to two equivalents of ethyl acrylate. 87 Figure 3.10. Higher reactivity of secondary amines in aza-Michael addition reactions...89 Figure 3.11. Acid catalyzed aza-Michael addition............................................................90 Figure 3.12. Acid catalyzed aza-Michael addition to activated alkyne acceptors. ...........91 Figure 3.13. Lewis acid catalyzed aza-Michael reaction..................................................93 Figure 3.14. Stereoselective aza-Michael additions..........................................................94 Figure 3.15. Regioselective Michael addition through preferential coordination of

substrate carbonyls with lithium cations,..................................................................97 Figure 3.16. Poly(amido amine) synthesis via a) primary and b) secondary amines. ....102 Figure 3.17. Poly(amino ester) synthesis from butanediol diacrylate and piperazine. ...110 Figure 3.18. Poly(imido sulfide) synthesis from a bismaleimide precursor and hydrogen

xxiii

sulfide gas. ..............................................................................................................113 Figure 3.19. a) A typical poly(imido sulfide)s synthesis. ...............................................116 Figure 3.20. Thermally stable poly(aspartamide)s synthesized from arylene ether diamines.

.................................................................................................................................119 Figure 3.21. Typical poly(amide aspartamide) polymerization. .....................................122 Figure 3.22. Poly(amino quinone) synthesis involving peracetic acid as an oxidizing agent.

.................................................................................................................................124 Figure 3.23. Polymerization of poly(thiophenylene)s via Michael addition and oxidation.

.................................................................................................................................126 Figure 3.24. Poly(enone sulfide) synthesis via Michael addition step growth. ..............130 Figure 3.25. Hydrogen transfer polymerization of acrylamide to poly(β-alanine).........131 Figure 3.26. Anionic polymerization of methyl methacrylate from diphenylhexyl lithium.

.................................................................................................................................135 Figure 3.27. Michael addition of heterocyclic nucleotide bases to acrylated anionic

polystyrene..............................................................................................................138 Figure 3.28. Polymerization of macrocyclic ether acrylic monomers to form ion channels.

.................................................................................................................................140 Figure 3.29. Group transfer polymerization of methyl methacrylate. ............................142 Figure 3.30. Water-initiated polymerization of ethyl α-cyanoacrylate...........................144 Figure 3.31. Synthesis of a dihydroxyl functional ATRP initiator. .................................147 Figure 3.32. Divergent PAMAM dendrimer synthesis via alternating Michael addition

and amidation..........................................................................................................150 Figure 3.33. Synthesis of PPI dendrimers via alternating Michael addition and

hydrogenation. ........................................................................................................154 Figure 3.34. Convergent dendrimer synthesis via dendron core-linking Michael addition

reactions. .................................................................................................................156 Figure 3.35. Crosslinkable dendrimer synthesis using Michael addition reactions........158 Figure 3.36. Hyperbranched polymer synthesis via AB2 Michael addition polymerization.

.................................................................................................................................161 Figure 3.37. Hyperbranched poly(aspartamide)s via A2 + B3 polymerization. ..............163 Figure 3.38. Hyperbranched poly(ester amine)s from A2 + B3 polymerization with

unequal reactivity in the B3 monomer functional groups. ......................................166 Figure 3.39. Homopolymerization of an AB2 poly(amido amine) monomer. ................169 Figure 3.40. Homopolymerization of an AB2 poly(ester ether) monomer......................171 Figure 3.41. Graft copolymerization via grafting of thiol terminated PEG to pendant

acryloxy side groups on a poly(ε-caprolactone) derivative. ...................................174 Figure 3.42. Modification of chitin via Michael addition reaction with ethyl acrylate. .176 Figure 3.43. Crosslinking of bismaleimide networks via a combination of Michael

addition and maleimide homopolymerization. .......................................................179 Figure 3.44. Carbon-Michael addition polymerization of acetoacetates with acrylates

catalyzed by bases for network synthesis. ..............................................................182 Figure 3.45. Network formation of PEG bis(vinyl sulfone) and protein dithiols. ..........192 Figure 3.46. a) Effect of pH on gel time for PEG bis(vinyl sulfone)..............................194 Figure 3.47. Release of albumin from PEG networks based on PEG tetraacrylate (black

xxiv

squares) and PEG octaacrylate (white triangles). ...................................................197 Figure 3.48. Protein-containing PEG networks via Michael addition crosslinking of PEG

octaacrylate with dithiothreitol. ..............................................................................199 Figure 3.49. a) Swelling of PEG octaacrylate, dithiothreitol networks via initial solvent

uptake followed by ester hydrolysis leading to degradation...................................200 Figure 3.50. Illustration of the stepwise synthesis of a PEG-based hydrogel by reacting

multiarm vinyl sulfone-terminated PEG with small amounts of a monocysteine-containing adhesion peptide ............................................................203

Figure 3.51. Self-condensing dendrimer synthesized from PPI and acrylate initiated living PTMO. ....................................................................................................................206

Figure 3.52. Protein incorporation via Michael addition of thiol residues to PEG-acrylamide......................................................................................................211

Figure 3.53. Drug delivery via polymer-drug conjugates...............................................213 Figure 4.1. Synthesis and polymerization from Uracil-TEMPO and Uracil-DEPN.......233 Figure 4.2. In-situ FTIR kinetic plot of styrene and n-butyl acrylate polymerizations using

Uracil-TEMPO and Uracil-DEPN ..........................................................................240 Figure 4.3. Evolution of molecular weight with conversion for the polymerizations of

styrene and n-butyl acrylate ....................................................................................243 Figure 4.4. Chemical shift of uracil N-H protons as a function of molecular weight in

CDCl3 at 10.4 wt%..................................................................................................246 Figure 4.5. Zero-shear melt viscosities for uracil functionalized poly(n-butyl acrylate)

.................................................................................................................................249 Figure 4.6. Arrhenius analysis of the melt rheology data depicting the flow activation

energies for functionalized and non functionalized poly(n-butyl acrylate) ............250 Figure 4.7. Thermogravimetric and derivative traces for a polystyrene synthesized from

Uracil-TEMPO........................................................................................................252 Figure 5.1. Synthesis of adenine and thymine nucleobase-functionalized triblock

copolymers..............................................................................................................264 Figure 5.2. Synthesis of DEPN2, difunctional alkoxyamine initiator, using

copper-promoted reaction of an activated dihalide.................................................273 Figure 5.3. SEC analysis of polymerization with time of n-butyl acrylate from DEPN2 and

linear molecular weight versus conversion plot......................................................276 Figure 5.4. SEC trace from a polymerization containing DEPN2 (difunctional) and

Sty-DEPN (monofunctional) initiators. ..................................................................278 Figure 5.5. Solution rheology of hydrogen bonding block copolymers (A3, T3 and their

blend) in chloroform at 25 oC. ................................................................................284 Figure 5.6. Zero-shear solution viscosities of the A3, T3 hydrogen bonding block

copolymers and their 1:1 A:T blend A3/T3 as a function of concentration............287 Figure 5.7. Dynamic mechanical storage modulus and tan delta curves for adenine- and

thymine-functionalized block copolymers..............................................................290 Figure 5.8. Expansion of high-temperature region of DMA storage modulus curves....291 Figure 5.9. Tapping mode AFM phase images of thymine- (T2) and

adenine-functionalized (A2) polymers before and after annealing.........................294 Figure 5.10. Tapping mode AFM phase images of A1, T1 and A1/T1 blend. ................297

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Figure 5.11. SAXS scattering profiles for nucleobase-containing polymers (A1, T1) and their 1:1 A:T blend. .................................................................................................302

Figure 5.12. Effect of annealing conditions on thymine-containing triblock copolymer (T1) sample. Scattering maxima in terms of q/q* are denoted with arrows. ..................304

Figure 5.13. Chemical shift changes during introduction of 9-octyladenine to a thymine-containing triblock copolymer (T3)..........................................................307

Figure 5.14. Tapping mode AFM images of unannealed thymine-functionalized block copolymer (T2) spin coated on a silicon wafer from chloroform solutions containing (a) 0, (b) 0.4 and (c) 2.2 equivalents of 9-octyladenine..........................................309

Figure 6.1. Reversible attachment of UP+ phosphonium salt to complementary nucleobase functionalized block copolymers. ...........................................................................314

Figure 6.2. ORTEP X-ray crystal structure of DEPN2 difunctional alkoxyamine initiator.................................................................................................................................324

Figure 6.3. Number average molecular weight as a function of monomer conversion for the polymerization of n-butyl acrylate with DEPN2 ...............................................325

Figure 6.4. Synthesis of adenine containing triblock copolymers from DEPN2 initiated poly(n-butyl acrylate)..............................................................................................327

Figure 6.5. DSC thermograms of adenine-containing block copolymer/UP+ blend.......329 Figure 6.6. Tapping mode AFM phase images of 1.5K-16.5K-1.5K adenine triblock UP+

blend (A:U 1:1) .......................................................................................................331 Figure 6.7. Small-angle X-ray scattering (SAXS) of 1.5K-16.5K-1.5K adenine triblock

and UP+ blend .........................................................................................................332 Figure 6.8 Bright field TEM micrograph of adenine-containing polymer/UP+ blend stained

with OsO4................................................................................................................333 Figure 6.9 Dynamic mechanical temperature sweep for pure 1.5K-16.5K-1.5K adenine

triblock copolymer and blend with 1 equivalent of UP+.........................................335 Figure 7.1. Synthesis of acetoacetate networks from acetoacetate functionalized PPG

(PPG bisAcAc) using DBU as a basic catalyst.......................................................341 Figure 7.2. Gel times for PPG bisAcAc / PEG diacrylate networks as a function of PPG

molecular weight.....................................................................................................350 Figure 7.3. Storage modulus (E’) plots for the PPG bisAcAc / PEG diacrylate networks

with a 1.4:1.0 acrylate to acetoacetate ratio............................................................355 Figure 7.4. Glass transition temperatures of PPG bisAcAc / PEG diacrylate networks as a

function of inverse PPG molecular weight as determined by SEC (1.4:1.0 acrylate to acetoacetate ratio) ...................................................................................................356

Figure 7.5. Stress-strain curves for PPG bisAcAc / PEG diacrylate networks containing 1.4:1.0 acrylate to acetoacetate ratios. Measurement was performed at 25 oC.......358

Figure 7.6. SEC traces from a PPG bisAcAc / PEG diacrylate crosslinking reaction....365 Figure 7.7. Weight-average molecular weight as determined by SEC MALLS and

refractive index versus acrylate conversion............................................................366 Figure 7.8. First-order rate analysis of acrylate concentration .......................................369 Figure 8.1. 1H NMR spectrum of acid-cleavable diacrylate crosslinker, DCDA. ..........381 Figure 8.2. Synthesis of crosslinked networks via base catalyzed Michael addition. ....382 Figure 8.3. Degradation reactions of Michael addition networks containing DCDA using

xxvi

p-toluenesulfonic acid.............................................................................................384 Figure 8.4. Pictures of the degradation of DCDA containing Michael addition networks

using p-toluenesulfonic acid ...................................................................................385 Figure 8.5. Thermogravimetric analysis (TGA) and derivative weight loss curve for

DCDA containing network. ....................................................................................387 Figure 8.6. Dynamic mechanical analysis (DMA) of acid cleavable diacrylate network.

.................................................................................................................................389 Figure 8.7. Tensile analysis of acid-cleavable Michael addition network. .....................391 Figure 9.1. Synthesis of sulfonated block copolymers via sequential addition anionic

polymerization ........................................................................................................407 Figure 9.2. SEC analysis of aliquots removed from the polymerization reaction after each

block (9K sample)...................................................................................................408 Figure 9.3. Dynamic mechanical analysis of sulfonated SEPS polymers ......................412 Figure 9.4. Glass transition temperatures of sodium sulfonated SEPS copolymers as a

function of rubber block molecular weight.............................................................414 Figure 9.5. Tensile curves for sulfonated SEPS block copolymers. ...............................416 Figure 9.6. Typical tensile curve and fit from the model by van der Heide. ..................420 Figure 9.7. Trends in fitting moduli and molecular weight between crosslinks for the

sodium sulfonated SEPS polymers. ........................................................................421 Figure 9.8 Complex viscosity (a) and storage modulus (b) master curves of 5K and 17K

samples (Tr = 20 oC). ..............................................................................................424 Figure 9.9. 1-D SAXS profiles for sulfonated block copolymers of varying rubber block

molecular weights ...................................................................................................427 Figure 9.10. Effect of neutralization on the scattering maxima in the sulfonated block

copolymer (10K sample).........................................................................................430 Figure 9.11. Tapping mode AFM phase images of the sulfonated block copolymer series.

.................................................................................................................................433 Figure 10.1. Ureidopyrimidone (UPy) quadruple hydrogen bonded dimer attached to

poly(ethylene-co-propylene)s. ................................................................................439 Figure 10.2. Representation of expected modes of association for different hydrogen

bonding architectures in solution. ...........................................................................449 Figure 10.3. SAXS data for UPy-containing monofunctional (left chart) and telechelic

(right chart) poly(ethylene-co-propylene)s polymers. ............................................452 Figure 10.4. SAXS data showing the effect of functionality for 12 kg/mol polymers. ..456 Figure 10.5. Scattering profile for star-shaped poly(ethylene-co-propylene) with UPy

functional periphery and the 12K monofunctional polymer...................................457 Figure 10.6. Variable temperature tapping mode AFM images of the UPy star-shaped

polymer. ..................................................................................................................460 Figure 11.1. Molecular recognition of uracil containing phosphonium salt with

complementary hydrogen bonding block copolymer..............................................467 Figure 11.2. Synthesis of hydrogen bonding triblock copolymers containing adenine and

thymine nucleobases from difunctional DEPN terminated poly(n-butyl acrylate).473 Figure 11.3. Tapping mode AFM a) height and b) phase images of adenine containing

polymer spin coated on Si, from chloroform solution. ...........................................476

xxvii

Figure 11.4. Changes in frequency (7th overtone) with exposure to humid air, 25 oC....478 Figure 11.5. Changes in frequency (7th overtone) with exposure to UPPh3

+ in water (0.5 wt%), 25 oC for adenine-containing and control block copolymer.........................482

Figure 11.6. Molecular structure of UPPh3+ (50% probability displacement ellipsoids),

crystallized from ethanol.........................................................................................485 Figure 11.7. Molecular structure of UPPh3

+ (50% probability displacement ellipsoids), crystallized from water/THF. ..................................................................................487

Figure 12.1. Synthesis of polystyrene diesters from DEPN2 initiator.............................499 Figure 12.2. Removal of DEPN endgroups via heating with 1-dodecanethiol...............502 Figure 12.3. 1H NMR spectrum of polystyrene diester (a) after removal of DEPN.......503 Figure 12.4. 31P NMR data showing loss of DEPN from polystyrene diester ................504 Figure 12.5. TGA data showing loss of DEPN endgroup...............................................505 Figure 12.6. Synthesis of graft polyester containing polystyrene arms. .........................507 Figure 12.7. 1H NMR spectrum of polyester graft copolymer (400 MHz, acetone-d6)..508 Figure 12.8. Graft polyester synthesis involving 1,4-cyclohexanedimethanol...............509 Figure 12.9. AFM a) height and b) phase images of a graft polyester with polystyrene arms

Mn = 5700 g/mol. ....................................................................................................511 Figure 13.1. Polymerization of a hydrogen bonded complex of a chiral auxiliary and a

complementary hydrogen bonding monomer .........................................................518 Figure 13.2. Synthesis of a chloroform soluble chiral auxiliary (AdHex) for

polymerization of complementary thymine or uracil-containing monomers. ........524 Figure 13.3. Polymerization of 1-vinylbenzylthymine with and without added chiral

auxiliary AdHex. .....................................................................................................527 Figure 13.4. 1H NMR spectra of poly(1-vinylbenzylthymine) .......................................528 Figure 13.5. Synthesis of 1-vinylthymine.......................................................................531 Figure 13.6. 1H NMR spectrum of poly(1-vinylthymine) polymerized in the presence (a)

and absence (b) of AdHex.......................................................................................533 Figure 14.1. Pictorial representation of ionic groups hydrogen bonded to a polymer chain

.................................................................................................................................541 Figure 14.2. Synthesis of an adenine-containing random copolymer. ............................547 Figure 14.3. Synthesis of a phosphonium styrene containing random copolymer. ........549 Figure 14.4. DSC analysis of phosphonium styrene copolymer (30 mol%). .................551 Figure 14.5. Small-angle X-ray scattering of 30 mol% phosphonium copolymer. ........553 Figure 14.6. DMA analysis of 30 mol% phosphonium copolymer.................................556 Figure 14.7. DSC analysis of blends of adenine- and phosphonium-functional random

copolymers and blend of adenine copolymer with uracil phosphonium salt..........558 Figure 14.8. Rheological analysis of uracil phosphonium salt blend with adenine

copolymer and comparisons with adenine and phosphonium copolymers.............560

1

Chapter 1. Introduction

1.1 Scientific Rationale and Perspective

Recently, increasing attention has been devoted to the study of non-covalent

interactions, particularly hydrogen bonding, in the construction and design of supramolecular

materials.1,2 Hydrogen bonding enables the introduction of thermoreversible properties into

macromolecules through the creation of specific non-covalent intermolecular interactions.3

The strength of these interactions is a strong function of temperature, solvent, humidity and

pH, thus allowing control of properties through a number of environmental parameters. The

strength of hydrogen bonding associations is further tunable via structural parameters and

molecular design of the hydrogen bonding sites. Association strengths range from DNA

nucleobases, which have association constants near 100 M-1, 4 to self-complementary

ureidopyrimidone (UPy) hydrogen bonding groups, which possess association constants near

107 M-1.1

Hydrogen bonding interactions are important for the development of self-assembling

supramolecular materials, which are defined as materials in which monomeric units are

reversibly bound via secondary interactions to form polymer-like structures that exhibit

1 Brunsveld, L.; Folmer, B. J. B.; Meijer, E. W.; Sijbesma, R. P. Supramolecular Polymers. Chem Rev 2001, 101, 4071-98. 2 Ilhan, F.; Galow, T. H.; Gray, M.; Clavier, G.; Rotello, V. M. Giant Vesicle Formation through Self-Assembly of Complementary Random Copolymers. J Am Chem Soc 2000, 122, 5895-6. 3 Yamauchi, K.; Lizotte, J. R.; Hercules, D. M.; Vergne, M. J.; Long, T. E. Combinations of Microphase Separation and Terminal Multiple Hydrogen Bonding in Novel Macromolecules. J Am Chem Soc 2002, 124, 8599-604. 4 Kyogoku, Y.; Lord, R. C.; Rich, A. The Effect of Substituents on the Hydrogen Bonding of Adenine and Uracil Derivatives. Proc Natl Acad Sci USA 1967, 57, 250-7.

2

polymeric properties in solution as well as in bulk.5 Researchers have used hydrogen bond

functional polymers to direct the formation of large vesicles,6 reversibly attach polymers on

surfaces, 7 and reversibly attach functional small molecules on polymers. 8 Long has

incorporated quadruple hydrogen bonding self-complementary UPy multiple hydrogen

bonding groups into random copolymers9 and also onto the chain end of homopolymers10 to

introduce controlled rheological performance and thermoreversible properties into novel

supramolecular structures.

In classical polymer science, hydrogen bonding interactions have already played a

major role. From the hydrogen bonding in polyurethanes 11 to the structures of

polypeptides12 we can observe the cohesive effect hydrogen bonding interactions produce in

macroscopic properties. More recently, elegant hydrogen bonding arrays were introduced

into synthetic polymers and have yielded novel materials containing reversible linkages,

5 Brunsveld, L.; Folmer, B. J. B.; Meijer, E. W.; Sijbesma, R. P. Supramolecular Polymers. Chem Rev 2001, 101, 4071-98. 6 Ilhan, F.; Galow, T. H.; Gray, M.; Clavier, G.; Rotello, V. M. Giant Vesicle Formation through Self-Assembly of Complementary Random Copolymers. J Am Chem Soc 2000, 122, 5895-6. 7 Norsten, T. B.; Jeoung, E.; Thibault, R. J.; Rotello, V. M. Specific Hydrogen-Bond-Mediated Recognition and Modification of Surfaces Using Complementary Functionalized Polymers. Langmuir 2003, 19, 7089-93. 8 Ilhan, F.; Gray, M.; Rotello, V. M. Reversible Side Chain Modification through Noncovalent Interactions. "Plug and Play" Polymers. Macromolecules 2001, 34, 2597-601. 9 Yamauchi, K.; Lizotte, J. R.; Long, T. E. Thermoreversible Poly(alkyl acrylates) Consisting of Self-Complementary Multiple Hydrogen Bonding. Macromolecules 2003, 36, 1083-8. 10 Yamauchi, K.; Lizotte, J. R.; Hercules, D. M.; Vergne, M. J.; Long, T. E. Combinations of Microphase Separation and Terminal Multiple Hydrogen Bonding in Novel Macromolecules. J Am Chem Soc 2002, 124, 8599-604. 11 McKeirnan, R. L.; Heintz, A. M.; Hsu, S. L.; Atkins, E. D. T. P., J; Gido, S. P. Influence of Hydrogen Bonding on the Crystallization Behavior of Semicrystalline Polyurethanes. Macromolecules 2002, 35, 6970-4. 12 Aggeli, A.; Bell, M.; Boden, N.; Keen, J. N.; Knowles, P. F.; McLeish, T. C. B.; Pitkeathly, M.; Radford, S. E. Responsive gels formed by the spontaneous self-assembly of peptides into polymeric β-sheet tapes Nature 1997, 386, 259-62.

3

which are tuned with such environmental variables as temperature, moisture and solvent

polarity. The resultant polymers often exhibit a stronger temperature dependence of melt

viscosity, suggesting possible processability advantages.

The advantages of hydrogen bond containing materials are numerous. Beyond the

novel rheological properties of hydrogen bonding systems, the introduction of hydrogen

bonds often results in increased modulus and tensile strength, as well as increased polarity

and adhesion. Hydrogen bonding interactions enable such diametrically opposed effects as

the compatibilization of blends and the induction of microphase separation. They can also be

used to create dynamic micelles in solution, the structure of which is tunable through the

introduction of guest molecules, altering solvent polarity or introducing covalent crosslinks.

In the case of block copolymers, the introduction of hydrogen bonding groups leads to a

synergistic combination of microphase separation and hydrogen bonding associations. This

results from associations between hydrogen bonding blocks, which reinforces microphase

separation. The microphase separation, in turn, leads to increased local concentration of the

hydrogen bonding groups in microphase separated domains, resulting in greater hydrogen

bonding interactions. Furthermore, guest molecules may be sequestered in specific domains

of the block copolymer allowing the reversible attachment of various functional groups.

In Chapter 2, we discuss the recent literature involving hydrogen bonding block and

telechelic polymers. Chapter 3 focuses on literature describing the applications of Michael

addition chemistry, which relates to the synthesis of covalent networks at ambient

temperature. Chapters 4 and 5 describe the introduction of nucleobases to synthetic polymers

and the resultant changes in properties which are observed. Chapter 6 and Chapter 11 discuss

4

the introduction of ionic guest molecules to hydrogen bonding polymers. Chapters 7 and 8

describe some of the research efforts involving Michael addition chemistry to synthesize

networks based on telechelic functional oligomers. Chapter 9 pertains to the synthesis of

sulfonated block copolymers, in which ionic interactions were studied. Chapter 10 discusses

the application of SAXS to analyze the morphology of telechelic hydrogen bonding polymers.

Chapter 12 presents efforts to utilize nitroxide mediated polymerization to create

macromonomers for polyester synthesis. Chapter 13 relates preliminary experiments toward

utilizing hydrogen bonding to influence stereocontrol in radical polymerizations. Chapter 14

centers on preliminary investigations of comparing covalent and hydrogen bonding

attachment of ionic groups.

5

Chapter 2. Review of the Literature – Hydrogen Bond Functionalized

Block Copolymers and Telechelic Hydrogen Bonding Oligomers

2.1 Fundamentals of Hydrogen Bonding

Hydrogen bonds are formed between molecules containing an electronegative atom

possessing lone pairs of electrons (usually O, N or F), called acceptors (A) and molecules

containing covalent bonds between hydrogen and an electronegative atom (usually O-H, N-H,

S-H), called donors (D). The polarized nature of the X-H bond (X=O,N..) results in a highly

electropositive hydrogen which is attracted toward bond formation with the electron rich

electronegative acceptor atoms.

The preferred geometry of the hydrogen bond is a linear conformation, with the

hydrogen atom positioned along the line connecting the heteroatoms. This preferred

geometry, however, is not always obtained in nature due to the constraints of the neighboring

covalent systems, which are much less easily distorted. This property of the hydrogen bond

leads to its directionality. The strength of individual hydrogen bonds range from 1-10

kcal/mol13 which leads to longer, weaker bonds compared to covalent bonds (70-110

kcal/mol). Thus, when hydrogen bonds serve as the primary secondary interaction, the

resultant structures are typically closer to thermodynamic equilibrium, and are quite dynamic

with respect to changes in the environment. This is due to the simple fact that thermal

energy (kT) more closely matches the bond strengths in these systems. For instance, an

association energy of 3 kcal/mol leads to a 1% level of dissociation among units in a single

13 Coleman, M. M.; Graf, J. F.; Painter, P. C., Specific Interactions and the Miscibility of Polymer Blends. Technomic: Lancaster, PA, 1991.

6

component bulk liquid bound with this energy at ambient temperature.14 This figure

obviously represents a time average; the typical lifetime of a hydrogen bond in water, for

example is roughly 10-11 s.15

The acidity of the donor and the Lewis basicity of the acceptor play important roles in

the strength of the interaction.16,17 Phenols, which possess a stronger acidity than aliphatic

alcohols, produce stronger hydrogen bonds with acceptors. These properties, which are

measured in terms of pKa or pKb, are founded in the electronic structure of the donors and

acceptors and their ability to stabilize negative or positive charges, respectively. Electron

withdrawing substituents such as fluorine increase the acidity of the hydrogen bond donors,

as the case of the hexafluoroisopropanol group.18 In the extreme case, mixing a strongly

acidic hydrogen bond donor with a strongly basic hydrogen bond acceptor results in an

acid-base neutralization reaction and the formation of an ion pair. Coleman et al. discussed

the fact that hydrogen bonding interactions are indeed founded in electrostatic attractive and

repulsive interactions.14

14 Coleman, M. M.; Graf, J. F.; Painter, P. C., Specific Interactions and the Miscibility of Polymer Blends. Technomic: Lancaster, PA, 1991. 15 Conde, O.; Teixerira, Hydrogen bond dynamics in water studied by depolarized Rayleigh scattering. J. J. Phys. 1983, 44, 525-9. 16 Beijer, F. H.; Sijbesma, R. P. V., J.A.J.M.; Meijer, E. W. K., H; Spek, A.L. Hydrogen-Bonded Complexes of Diaminopyridines and Diaminotriazines: Opposite Effect of Acylation on Complex Stabilities. J. Org. Chem. 1996, 61, 6371-80. 17 Kawakami, T.; Kato, T. Use of Intermolecular Hydrogen Bonding between Imidazolyl Moieties and Carboxylic Acids for the Supramolecular Self-Association of Liquid-Crystalline Side-Chain Polymers and Networks. Macromolecules 1998, 31, 4475-9. 18 Liu, S.; Zhu, H.; Zhao, H.; Jiang, M.; Wu, C. Interpolymer Hydrogen-Bonding Complexation Induced Micellization from Polystyrene-b-poly(methyl methacrylate) and PS(OH) in Toluene. Langmuir 2000, 16, 3712-7.

7

hydrogen bonding interaction

A-H B A-H B+ [2.1]

formation of ion pairs

A-H B A- BH++ + [2.2]

The common measure of the strength of association or complexation is the association

constant (Ka), defined in terms the equilibrium between associated and dissociated units:

A + B A-B Ka = [A-B][A][B] [2.3]

The Ka value is a key measurement of the strength of the hydrogen bonding association

and determines the dynamics of systems incorporating the hydrogen bonding groups. Thus,

for weaker hydrogen bonding interactions, the lifetimes of associated species are shorter than

for systems with higher association constants. This has a dramatic effect on material

properties, such as relaxation rates, creep, modulus, melt viscosity etc. In order to tune the

strength of the association constant, numerous molecular parameters are accessible. A

common approach for increasing association strength is the incorporation of additional

hydrogen bonding sites within a single hydrogen bonding array, termed “multiple hydrogen

bonding”. Entropically, the association of two species is unfavorable, but this loss of entropy

is not greatly increased from the association of additional pairs of donors and acceptors on

the same two molecules. Single through quadruple hydrogen bonding units exist and even

some cases of larger arrays containing six19 and eight20 hydrogen bonds were synthesized

19 Zeng, H.; Miller, R. S.; Flowers, R. A.; Gong, B. A Highly Stable, Six-Hydrogen-Bonded Molecular Duplex. J Am Chem Soc 2000, 122, 2635-44. 20 Folmer, B. J. B.; Sijbesma, R. P.; Kooijman, H.; Spek, A. L.; Meijer, E. W. Cooperative Dynamics in Duplexes of Stacked Hydrogen-Bonded Moieties. J Am Chem Soc 1999, 121, 9001-7.

8

and studied. Additionally, the strength of the hydrogen bonding interaction is tuned via the

pattern of hydrogen bonding groups. Meijer, Lehn and Rotello have shown that a number of

factors are important in the use of multiple hydrogen bonded systems.21,22 Alternation of

donor and acceptor groups in a multiple hydrogen bonding array reduces the strength of the

association via repulsive interactions of opposing adjacent donors or acceptors.23,24 Thus,

Meijer’s quadruple hydrogen bonding (DDAA) UPy group is designed with minimum

alternation of donor and acceptor units.23 When multiple hydrogen bonding groups are

considered, the possibility of self-complementarity arises. The simplest case of

self-complementarity is probably the carboxylic acid dimer, which contains two hydrogen

bonds. In contrast, complementary hydrogen bonding arrays are found in DNA, which

possesses both adenine-thymine (A-T) and cytosine-guanine (C-G) pairs. Another factor to

consider in heterocylic bases is the ability of the base to tautomerize into different forms.25

This can lead to complexity in the behavior of the hydrogen bonding group, and different

hydrogen bonding guests can shift the equilibrium between tautomers.26

The reversible nature of the hydrogen bond is not limited to thermoreversibility,

21 Beijer, F. H.; Sijbesma, R. P. V., J.A.J.M.; Meijer, E. W. K., H; Spek, A.L. Hydrogen-Bonded Complexes of Diaminopyridines and Diaminotriazines: Opposite Effect of Acylation on Complex Stabilities. J. Org. Chem. 1996, 61, 6371-80. 22 Brunsveld, L.; Folmer, B. J. B.; Meijer, E. W.; Sijbesma, R. P. Supramolecular Polymers. Chem Rev 2001, 101, 4071-98. 23 Beijer, F. H.; Sijbesma, R. P.; Kooijman, H.; Spek, A. L.; Meijer, E. W. Strong Dimerization of Ureidopyrimidones via Quadruple Hydrogen Bonding. J Am Chem Soc 1998, 120, 6761-9. 24 Jorgensen, W. L.; Pranata, J. Importance of Secondary Interactions in Triply Hydrogen Bonded Complexes: Guanine-Cytosine vs Uracil-2,6-Diaminopyridine. J Am Chem Soc 1990, 112, 2008-10. 25 Lee, G. Y. C.; Chan, S. I. Tautomerism of Nucleic Acid Bases. 11. Guanine. J Am Chem Soc 1972, 94, 3218-3229. 26 Ligthart, G. B. W. L.; Ohkawa, H.; Sijbesma, R. P.; Meijer, E. W. Complementary Quadruple Hydrogen Bonding in Supramolecular Copolymers. J Am Chem Soc 2005, 127, 810-811.

9

although that is the most commonly exploited and studied property of these systems. The

hydrogen bond is also sensitive to other environmental factors, such as the polarity of the

medium, and the presence of competitive solvents and water. Deans et al. observed that

solvent polarity has a strong effect on hydrodynamic volume for self-associating polymers.27

Thus, humidity and exposure to polar media are two other factors which are considerations in

the application of hydrogen bonded materials. Another factor that strongly affects hydrogen

bonding, as suggested in Eq. 1, is concentration. Lower concentrations of monomeric units

leads to lower equilibrium concentrations of complexed units. Solution pH can also affect

hydrogen bonding systems, leading to pH controlled thickening28 in cases of interpolymer

complexes between poly(acrylic acid) and poly(acrylamide). Complexes of poly(acrylic acid)

and poly(N-vinylpyrrolidone) exhibit molecular weight dependent critical pHs below which

stable complexes are formed due to a transition to polyelectrolyte species at higher pH.29

The hydrogen bond is extensively used in nature, particularly in the construction of

proteins,30 DNA31 and RNA. In all cases, it performs the role of establishing a reversible

structure which allows such processes as replication and transcription in DNA and reactions

in enzymes and is key in many molecular recognition events in living organisms. One goal

of modern science is to incorporate such functionality and dynamics into synthetic materials.

27 Deans, R.; Ilhan, F.; Rotello, V. M. Recognition-Mediated Unfolding of a Self-Assembled Polymeric Globule. Macromolecules 1999, 32, 4956-60. 28 Sotiropoulou, M.; Bokias, G.; Staikos, G. Soluble Hydrogen-Bonding Interpolymer Complexes and pH-controlled Thickening Phenomena in Water. Macromolecules 2003, 36, 1349-54. 29 Nurkeeva, Z. S.; Mun, G. A.; Khutoryanskiy, V. V.; Bitekenova, A. B.; Dubolazov, A. V.; Esirkegenova, S. Z. Eur. Phys. J 2003, 10, 65-8. 30 Aggeli, A.; Bell, M.; Boden, N.; Keen, J. N.; Knowles, P. F.; McLeish, T. C. B.; Pitkeathly, M.; Radford, S. E. Responsive gels formed by the spontaneous self-assembly of peptides into polymeric β-sheet tapes Nature 1997, 386, 259-62. 31 Voet, D.; Voet, J. G., Biochemistry. John Wiley and Sons: New York, 1995; p 1361.

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In the case of DNA, hydrogen bonding performs in concert with numerous other

non-covalent interactions such as electrostatic interactions and π-π stacking32 to yield the

double helix structure and to give DNA its dynamic properties.

Numerous analytical tools are useful in the study of hydrogen bonding phenomenon.

FTIR33 and NMR34 techniques as well as UV-vis35 are useful for determining association

constants or observing association phenomena. For very high association constant systems,

more advanced techniques are requisite.36 Rheology37,38 and mechanical analysis39 are

useful for determining the influence of hydrogen bonding interactions on thermal and

mechanical properties, while microscopy (TEM, AFM) are primarily useful for studying

changes in morphology. Solution rheology is a particularly useful tool for hydrogen bonded

systems due to the ability to introduce solvents of varying dielectric constant and to study the

32 Vanommeslaeghe, K.; Mignon, P.; Loverix, S.; Tourwe, D.; Geerlings, P. Influence of Stacking on the Hydrogen Bond Donating Potential of Nucleic Bases. Journal of Chemical Theory and Computation 2006, 2, 1444-52. 33 Kyogoku, Y.; Lord, R. C.; Rich, A. The Effect of Substituents on the Hydrogen Bonding of Adenine and Uracil Derivatives. Proc Natl Acad Sci USA 1967, 57, 250-7. 34 Fielding, L. Determination of Association Constants (Ka) from Solution NMR Data. Tetrahedron 2000, 56, 6151-70. 35 Lutz, J. F.; Thunemann, A. F.; Rurack, K. DNA-like “Melting” of Adenine- and Thymine-Functionalized Synthetic Copolymers. Macromolecules 2005, 38, 8124-6. 36 Söntjens, S. H. M.; Sijbesma, R. P.; van Genderen, M. H. P.; Meijer, E. W. Stability and Lifetime of Quadruply Hydrogen Bonded 2-Ureido-4[1H]-pyrimidinone Dimers. J Am Chem Soc 2000, 122, 7487-93. 37 Yamauchi, K.; Lizotte, J. R.; Hercules, D. M.; Vergne, M. J.; Long, T. E. Combinations of Microphase Separation and Terminal Multiple Hydrogen Bonding in Novel Macromolecules. J Am Chem Soc 2002, 124, 8599-604. 38 Müller, M.; Dardin, A.; Seidel, U.; Balsamo, V.; Ivan, B.; Spiess, H. W.; Stadler, R. Junction Dynamics in Telechelic Hydrogen Bonded Polyisobutylene Networks. Macromolecules 1996, 29, 2577-83. 39 Reith, R. L.; Eaton, F. R.; Coates, W. G. Polymerization of Ureidopyrimidinone-Functionalized Olefins by Using Late-Transition Metal Ziegler-Natta Catalysts: Synthesis of Thermoplastic Elastomeric Polyolefins. Angew. Chem. Int. Ed. 2001, 40, 2153-6.

11

hydrogen bonding interaction as a function of concentration.40 Light scattering techniques

(DLS, SLS) are often used to characterize micellar or aggregate structures resulting from

hydrogen bonding associations in solution.41,42

2.2 Performance Advantages of Hydrogen Bonding Polymers

Reversibility of the hydrogen bond confers unique properties to polymeric and

supramolecular materials. In supramolecular science, reversible bonding is important

because it allows the self assembly process to occur. Molecular recognition and

self-organization are hailed as the mechanisms of supramolecular growth.43 Controlled

geometric placement of hydrogen bonding groups leads to efficient molecular recognition

which is optimized through self-organization. Furthermore, the directionality of the

hydrogen bond assists in the construction of supramolecular structures since random

orientations of hydrogen bonding associations leading to disordered networks are not favored.

In the field of polymer processing, thermoreversibility is of interest because of the promise

for lower melt viscosities of hydrogen bonding polymers. Thus, a lower molecular weight

hydrogen bonding polymer could potentially afford mechanical properties approaching those

of a higher molecular weight non-functional polymer over a short time scale and yet exhibit

40 Sijbesma, R. P.; Beijer, F. H.; Brunsveld, L.; Folmer, B. J. B.; Hirschberg, J. H. K. K.; Lange, R. F. M.; Lowe, J. K. L.; Meijer, E. W. Reversible Polymers Formed from Self-Complementary Monomers Using Quadruple Hydrogen Bonding. Science 1997, 278, 1601-4. 41 Liu, G.; Zhou, J. First- and Zero-Order Kinetics of Porogen Release from the Cross-Linked Cores of Diblock Nanospheres. Macromolecules 2003, 36, 5279-84. 42 Liu, L.; Jiang, M. Synthesis of Novel Triblock Copolymers Containing Hydrogen-Bond Interaction Groups via Chemical Modification of Hydrogenated Poly (styrene-block-butadiene-block-styrene). Macromolecules 1995, 28, 8702-4. 43 Kato, T. Supramolecular liquid-crystalline materials: molecular self-assembly and self-organization through intermolecular hydrogen bonding. Supramolecular Science 1996, 3, 53-9.

12

lower melt viscosity when heated above the dissociation temperature of the hydrogen

bonding groups.44,45 The hydrogen bonding polymer would exhibit a higher apparent

molecular weight at room temperature according to viscosity measurements than it actually

possessed.

In the case of ditopic molecules with two hydrogen bonding groups, linear non-covalent

polymers can form in either solution or the solid state (Figure 2.1). In this case, the degree of

non-covalent polymerization (DP) depends directly on the association constant (Ka) in the

medium and the concentration of the molecule (c):46

DP = 4Kac/(-1+(1+8Kac)0.5) ~ (2Kac)0.5 [2.4]

44 Yamauchi, K.; Lizotte, J. R.; Hercules, D. M.; Vergne, M. J.; Long, T. E. Combinations of Microphase Separation and Terminal Multiple Hydrogen Bonding in Novel Macromolecules. J Am Chem Soc 2002, 124, 8599-604. 45 Yamauchi, K.; Kanomata, A.; Inoue, T.; Long, T. E. Thermoreversible Polyesters Consisting of Multiple Hydrogen Bonding (MHB). Macromolecules 2004, 37, 3519-22. 46 Xu, J.; Fogleman, E. A.; Craig, S. L. Structure and Properties of DNA-Based Reversible Polymers. Macromolecules 2004, 37, 1863-70.

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Figure 2.1. Degree of non-covalent polymerization as a function of association constant (Ka).

The effect of concentration is illustrated in the two parallel lines. Reprinted with permission

from Brunsveld et al.47 Copyright 2001 American Chemical Society.

47 Brunsveld, L.; Folmer, B. J. B.; Meijer, E. W.; Sijbesma, R. P. Supramolecular Polymers. Chem Rev 2001, 101, 4071-98.

14

Another feature of hydrogen bonding systems is that they are dynamic, and this often

allows them to achieve the most thermodynamically favored state. This dynamic property

of hydrogen bonding allows self-assembly to occur at ambient conditions, unlike many

covalent polymerizations.48 Rotello et al. were able to create a thermodynamic cycle to

examine the competitive processes of self association of a hydrogen bonding polymer and

association with a small molecule complementary guest in solution.49 In the case of

hydrogen bonded networks, the dynamic character leads to the presence of fewer network

defects, such as dangling ends and unincorporated chains (sol). In support of this hypothesis,

Meijer et al. observed a higher plateau modulus for a hydrogen bonded network compared to

a covalent network.50

Hydrogen bonding has improved mechanical properties in a number of systems and is

often grouped with other non-covalent cohesive intermolecular interactions, performing the

“glue” that sticks chains. Hydrogen bonding supramolecular assembly in conjunction with

covalent polymer synthesis often leads to positive impact on mechanical properties such as

stress at break and percent elongation51 as well as elastic modulus.52 Nissan theorized that

for a solid in which hydrogen bonds dominate the mechanical properties such as ice or

48 Saadeh, H.; Wang, L.; Yu, L. Supramolecular Solid-State Assemblies Exhibiting Electrooptic Effects. J Am Chem Soc 2000, 122, 546-7. 49 Deans, R.; Ilhan, F.; Rotello, V. M. Recognition-Mediated Unfolding of a Self-Assembled Polymeric Globule. Macromolecules 1999, 32, 4956-60. 50 Lange, R. F. M.; van Gurp, M.; Meijer, E. W. Hydrogen-bonded supramolecular polymer networks. J. Polym. Sci. Part A. Polym. Chem. 1999, 37, 3657-70. 51 Reith, R. L.; Eaton, F. R.; Coates, W. G. Polymerization of Ureidopyrimidinone-Functionalized Olefins by Using Late-Transition Metal Ziegler-Natta Catalysts: Synthesis of Thermoplastic Elastomeric Polyolefins. Angew. Chem. Int. Ed. 2001, 40, 2153-6. 52 Shandryuk, G. A.; Kuptsov, S. A.; Shatalova, A. M.; Plate, N. A.; Talroze, R. V. Liquid Crystal H-Bonded Polymer Networks under Mechanical Stress. Macromolecules 2003, 36, 3417-23.

15

cellulose, that the Young’s modulus scales with the number of hydrogen bonds per unit

volume to the 1/3 power. 53 Hydrogen bonding results in increased glass transition

temperature, due to restricted molecular mobility and temporary “crosslinks”.54 Hydrogen

bonding interactions are credited, in part (along with phase separation), with the outstanding

mechanical properties of polyurethanes. Wilkes and coworkers have recently shown that

hydrogen bonding in model single unit hard segment poly(urethane urea)s leads to the

development of ribbon-like hard phases containing stacks of hydrogen bonding urethanes or

ureas which are disrupted upon addition of branching units in the hard phase or addition of

hydrogen bond screening agents such as lithium chloride.55 Further studies of single hard

segment poly(urethane)s and poly(urea)s demonstrated that the symmetry of the hard

segment precursor, which affects the packing ability of hydrogen bonding groups, have a

dramatic influence on the thermal integrity of the hard phases. Model poly(urea)s based on

p-phenylene diisocyanate and poly(tetramethylene oxide) possessed rubbery plateaus

extending to 250 oC, while meta substitution led to rubbery plateaus extending only 100 oC.56

McKeirnan et al. utilized variable temperature FTIR to show that the hydrogen bonds in

polyurethanes persist up to temperatures beyond 100 oC and that, even in the melt, ~ 75% of

53 Nissan, A. H. H-Bond Dissociation in Hydrogen Bond Dominated Solids. Macromolecules 1976, 9, 840-50. 54 Yamauchi, K.; Lizotte, J. R.; Hercules, D. M.; Vergne, M. J.; Long, T. E. Combinations of Microphase Separation and Terminal Multiple Hydrogen Bonding in Novel Macromolecules. J Am Chem Soc 2002, 124, 8599-604. 55 Sheth, J. P.; Wilkes, G. L.; Fornof, A. R.; Long, T. E.; Yilgor, I. Probing the Hard Segment Phase Connectivity and Percolation in Model Segmented Poly(urethane urea) Copolymers. Macromolecules 2005, 38, 5681-5. 56 Sheth, J. P.; Klinedinst, D. B.; Wilkes, G. L.; Yilgor, E.; Yilgor, I. Role of chain symmetry and hydrogen bonding in segmented copolymers with monodisperse hard segments. Polymer 2005, 46, 7317-22.

16

the urethane linkages were involved in hydrogen bonding.57

Hydrogen bonding interactions confer unique melt 58 and solution 59 rheological

behavior. The temperature sensitivity of the hydrogen bond holds promise for increasing the

temperature dependence of the melt viscosity while providing an effectively higher molecular

weight at room temperature. Thus, lower molecular weight hydrogen bonding polymers may

be employed. However, increased melt and solution viscosity are typically observed at

temperatures where hydrogen bonds still exist. Lillya et al. showed that the zero-shear melt

viscosity of a 650 g/mol carboxylic acid terminated poly(tetrahydrofuran) was 2.5 times that

of the corresponding protected (ester) version telechelic carboxylic acid functionalized

poly(THF).60 This high melt viscosity dropped above 62 ºC and 50 ºC for the 650 g/mol and

the 1000 g/mol polymers respectively. Rowan et al. have also observed sudden decreases in

viscosity in hydrogen bonding systems.61 Based on sticky reptation theory that Leibler,

Rubinstein and Colby developed,62 the terminal relaxation time (tD) for a thermoreversible,

hydrogen bonded network is longer than for a corresponding non-functionalized polymer.

Rogovina et al. observed reversible network formation in self associating carboxyl

57 McKeirnan, R. L.; Heintz, A. M.; Hsu, S. L.; Atkins, E. D. T. P., J; Gido, S. P. Influence of Hydrogen Bonding on the Crystallization Behavior of Semicrystalline Polyurethanes. Macromolecules 2002, 35, 6970-4. 58 Yamauchi, K.; Lizotte, J. R.; Long, T. E. Thermoreversible Poly(alkyl acrylates) Consisting of Self-Complementary Multiple Hydrogen Bonding. Macromolecules 2003, 36, 1083-8 59 Lele, A. K.; Mashelkar, R. A. Energetically crosslinked transient network (ECTN) model: implications in transient shear and elongation flows. J. Non-Newtonian Fluid Mech. 1998, 75, 99-115. 60 Lillya, C. P.; Baker, R. J.; Huette, S.; Winter, H. H.; Lin, H.-G.; Shi, J.; Dickinson, L. C.; Chien, J. C. W. Linear Chain Extension through Associative Termini. Macromolecules 1992, 25, 2076-80. 61 Sivakova, S.; Bohnsak, D. A.; Mackay, M. E.; Suwanmala, P.; Rowan, S. J. Utilization of a Combination of Weak Hydrogen-Bonding Interactions and Phase Segregation to Yield Highly Thermosensitive Supramolecular Polymers. J Am Chem Soc 2005, 127, 18202-11. 62 Leibler, L.; Rubinstein, M.; Colby, R. H. Dynamics of reversible networks. Macromolecules 1991, 24, 4701-7.

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functionalized poly(dimethylcarbosiloxane) with 0.5-2.5 mol% of the carboxylic acid

group.63 Müller, Seidel and Stadler conducted some of the first major rheological studies of

multiple hydrogen bond functionalized polymers. They studied randomly functionalized,

urazole and phenylurazole containing, anionically synthesized polybutadienes.64 Increased

plateau shear moduli, melt viscosity and a shifting of relaxation times to lower frequencies

(longer times) were observed in randomly substituted urazole containing polybutadienes.65

Zero shear viscosities, which are sensitive to molecular weight, but not to molecular weight

distribution (MWD) were shown to increase with mol% phenylurazole substitution which

gave an increasing “effective” molecular weight. The real part of the creep compliance at

low shear rates (Jco), which is sensitive to changes in MWD but not to molecular weight was

found to increase with increasing phenylurazole content due to the effective broadening in

MWD in the thermoreversible network. Similar results were obtained from relaxation time

spectra, where a broadening of the relaxation time distribution occurred for phenylurazole

substituted polymers. Increased flow activation energies were also observed through fitting

of Williams-Landel-Ferry (WLF) parameters for the shift factors of the storage modulus.

Comparing plateau moduli above and below a frequency corresponding to the dissociation

rate of the phenylurazoles led to the determination of the number of reversible contacts

indicating that 60-70% of the phenyurazole groups were complexed at any one point in time.

63 Rogovina, L. Z.; Vasilev, V. G.; Papkov, V. S.; Shchegolikhina, O. I.; Slonimskii, G. L.; Zhdanov, A. A. The peculiarities of physical network formation in carboxyl-containing poly(dimethylcarbosiloxane). Macromol. Symp. 1995, 93, 135-42. 64 Müller, M.; Seidel, U.; Stadler, R. Influence of hydrogen bonding on the viscoelastic properties of thermoreversible networks: analysis of the local complex dynamics. Polymer 1995, 36, 3143-50. 65 De Lucca Freitas, L.; Stadler, R. Thermoplastic Elastomers by Hydrogen Bonding. 3. Interrelations between Molecular Parameters and Rheological Properties. Macromolecules 1987, 20, 2478-85.

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The solution behavior of hydrogen bonding polymers is equally interesting compared to

the solid state. In the dissolved state, polymers exhibit greater freedom to assume

conformations which are thermodynamically favored. Furthermore, the dynamic nature of

solutions allows rapid response to changes in environment. In solution, factors such as

concentration and solvent dielectric constant are used to control the equilibrium between

associated and dissociated states. For instance, Kwei et al. established that self-association of

the 4-hydroxystyrene residues in symmetric poly(styrene-b-4-hydroxystyrene) diblock

copolymers led to the formation of rod-like micelles in low polarity toluene which was not

observed in the more polar THF solvent.66 Reversible non-covalent crosslinking of similar

polymers with 1,4-butanediamine induced micelle formation. 67 Placement of specific

molecules within micelles was also achieved using hydrogen bonding.68 Solvent dielectric

constant strongly affects the solution rheological behavior of hydrogen bonding polymers.

Solution rheological studies of UPy functional PMMA indicated that the solution viscosity

increased with decreasing dielectric constant (polarity) of the solvent, and that the critical

concentration for entanglement (Ce) decreased, presumably due to the higher effective

molecular weight of the associated structures.69 Furthermore, the slope of the viscosity

versus concentration above Ce increased with decreasing solvent polarity, illustrating the

66 Zhao, J. Q.; Pearce, E. M.; Kwei, T. K.; Jeon, H. S.; Kesani, P. K.; Balsara, N. P. Micelles Formed by a Model Hydrogen-Bonding Block Copolymer. Macromolecules 1995, 28, 1972-8. 67 Yoshida, E.; Kunugi, S. Micelle Formation of Nonamphiphilic Diblock Copolymers through Noncovalent Bond Cross-Linking. Macromolecules 2002, 35, 6665-9. 68 Zhang, W.; Shi, L.; An, Y.; Wu, K.; Gao, L.; Liu, Z.; Ma, R.; Meng, Q.; Zhao, C.; He, B. Adsorption of Poly(4-vinyl pyridine) Unimers into Polystyrene-Block-Poly(acrylic acid) Micelles in Ethanol Due to Hydrogen Bonding. Macromolecules 2004, 37, 2924-9. 69 McKee, M. G.; Elkins, C.; Long, T. E. Influence of self-complementary hydrogen bonding on solution rheology/electrospinning relationships. Polymer 2004, 45, 8705-15.

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effect of concentration on the equilibrium between associated and dissociated states.

Hydrogen bonding was utilized to induce micelle formation. Chen and Jiang have studied

micelle formation via hydrogen bonding between homopolymers of poly(4-vinylpyridine)

and carboxylic acid terminated polystyrene or polyisoprene. They found that assemblies of

these homopolymers formed micelles when selective solvents were added for either block.70

The size of such micelles was controlled via the mass ratio of the two homopolymers.71

Furthermore, the polydispersity of the micelles changed with the solvent composition, and

narrowed for less selective solvent mixtures.

Other potential applications for hydrogen bonding polymers exist, such as reversible

attachment of guest molecules,72 reversible crosslinking,73 better melt processing behavior,74

self-healing materials,75 shape-memory polymers,76 recyclable thermosets,75 induction of

liquid crystallinity 77 induction of phase mixing 78 and demixing, 79 templated

70 Chen, D.; Jiang, M. Strategies for Constructing Polymeric Micelles and Hollow Spheres in Solution via Specific Intermolecular Interactions. Acc Chem Res 2005, 38, 494-502. 71 Wang, M.; Zhang, G.; Chen, D.; Jiang, M.; Liu, S. Noncovalently Connected Polymeric Micelles Based on a Homopolymer Pair in Solutions. Macromolecules 2001, 34, 7172-8. 72 Ilhan, F.; Gray, M.; Rotello, V. M. Reversible Side Chain Modification through Noncovalent Interactions. "Plug and Play" Polymers. Macromolecules 2001, 34, 2597-601. 73 Thibault, R. J.; Hotchkiss, P. J.; Gray, M.; Rotello, V. M. Thermally Reversible Formation of Microspheres through Non-Covalent Polymer Cross-Linking. J Am Chem Soc 2003, 125, 11249-52. 74 Yamauchi, K.; Lizotte, J. R.; Hercules, D. M.; Vergne, M. J.; Long, T. E. Combinations of Microphase Separation and Terminal Multiple Hydrogen Bonding in Novel Macromolecules. J Am Chem Soc 2002, 124, 8599-604. 75 Lange, R. F. M.; van Gurp, M.; Meijer, E. W. Hydrogen-bonded supramolecular polymer networks. J. Polym. Sci. Part A. Polym. Chem. 1999, 37, 3657-70. 76 Liu, G.; Guan, C.; Xia, H.; Guo, F.; Ding, X.; Peng, Y. Novel Shape-Memory Polymer Based on Hydrogen Bonding. Macromol Rapid Commun 2006, 27, 1100-4. 77 Gulik-Krzywicki, T.; Fouquey, C.; Lehn, J. M. Electron microscopic study of supramolecular liquid crystalline polymers formed by molecular-recognition-directed self-assembly from complementary chiral components. Proc. Natl. Acad. Sci. USA 1993, 90, 163-7. 78 Kuo, S. W.; Chan, S. C.; Chang, F. C. Correlation of Material and Processing Time Scales with Structure Development in Isotactic Polypropylene Crystallization. Macromolecules 2003, 36, 6653-61.

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polymerization,80 drug-selective chromatographic media,81 hydrogen bonded layer-by-layer

assemblies82 and reinforcement of orientation of non-linear optic materials.83

2.3 Hydrogen Bonding Block Copolymers

Hydrogen bonding telechelic and block copolymers both differ from randomly

functionalized copolymers in that the placement of the hydrogen bonding groups is localized

to specific region(s) in the polymer backbone. This typically leads to different behavior

compared to random functionalization due to the presence of both phase separation and

hydrogen bonding interactions. Thus, in the bulk state, many of these systems consist of

separated domains of hydrogen bonding groups or blocks and non-hydrogen bonded regions.

One particular advantage of introducing hydrogen bonding groups as substituents in one

particular block of a block copolymer structure is the multiplicative and cooperative effects

of the hydrogen bonding interactions due to the multitude of adjacent hydrogen bonding

groups. 84 Hogen-Esch et al. observed the association constants of

poly(4-vinylpyridine-b-NLO) with poly(4-hydroxystyrene-b-styrene) (a good hydrogen

79 de Lucca Freitas, L.; Jacobi, M. M.; Goncalves, G. Microphase Separation Induced by Hydrogen Bonding in a Poly(1,4-butadiene)-block poly(1,4-isoprene) Diblock Copolymers An Example of Supramolecular Organization via Tandem Interactions. Macromolecules 1998, 31, 3379-82. 80 Khan, A.; Haddleton, D. M.; Hannon, M. J.; Kukulj, D.; Marsh, A. Hydrogen Bond Template-Directed Polymerization of Protected 5'-Acryloylnucleosides. Macromolecules 1999, 32, 6560-4. 81 Kugimiya, A.; Mukawa, T.; Takeuchi, T. Synthesis of 5-fluorouracil-imprinted polymers with multiple hydrogen bonding interactions. Analyst 2001, 126, 772-4. 82 Wang, L.; Fu, Y.; Wang, Z.; Fan, Y.; Zhang, X. Investigation into an Alternating Multilayer Film of Poly(4-Vinylpyridine) and Poly(acrylic acid) Based on Hydrogen Bonding. Langmuir 1999, 15, 1360-3. 83 Huggins, K. E.; Son, S.; Stupp, S. I. Two-Dimensional Supramolecular Assemblies of a Polydiacetylene. 1. Synthesis, Structure, and Third-Order Nonlinear Optical Properties. Macromolecules 1997, 30, 5305-12. 84 Pan, J.; Chen, M.; Warner, W.; He, M.; Dalton, L.; Hogen-Esch, T. E. Synthesis and Self-Assembly of Diblock Copolymers through Hydrogen Bonding. Semiquantitative Determination of Binding Constants. Macromolecules 2000, 33, 7835-41.

21

bonding donor) of 4.5 to 7.9 x 105 M-1 and poly(2-hydroxyethyl methacrylate-b-methyl

methacrylate) (a poor hydrogen bonding donor) of 4.4 x 103 M-1 in toluene/CH2Cl2 (99:1)

mixtures. These values are much higher than those expected for a single

vinylpyridine-hydroxystyrene hydrogen bonding interaction. Brus et al. found that the

cooperativity of association of poly(4-vinyl pyridine) and poly(4-hydroxystyrene) increased

with degree of polymerization and reached a maximum at a 1:1 functional group molar

ratio.85

Also, only short hydrogen bonding blocks are necessary to achieve phase separation,

due to the influence of the associations on the tendency of block copolymers to microphase

separate. Although this tendency is often measured through the Flory-Huggins interaction

parameter χ,86, 87 hydrogen bonding interactions must be accounted for through additions of

other parameters into thermodynamic treatments, since χ refers to non-specific interactions

and is repulsive, whereas hydrogen bonding is attractive. Painter and Coleman have

thoroughly discussed thermodynamic treatments of hydrogen bonding effects in polymer

blend miscibility, and considerations must be made for screening and accessibility of

hydrogen bonding interactions (since they are directional) as well as the competition between

self-association and complementary association. 88 , 89 In some cases, single hydrogen

85 Kriz, J.; Dybal, J.; Brus, J. Cooperative Hydrogen Bonds of Macromolecules. 2. Two-Dimensional Cooperativity in the Binding of Poly(4-vinylpyridine) to Poly(4-vinylphenol). J Phys Chem B 2006, 110, 18338-46. 86 Leibler, L. Theory of Microphase Separation in Block Copolymers. Macromolecules 1980, 13, 1602-17. 87 Lee, K. M.; Han, C. D. Microphase Separation Transition and Rheology of Side-Chain Liquid-Crystalline Block Copolymers. Macromolecules 2002, 35, 3145-56. 88 Coleman, M.M.; Painter, P.C. Hydrogen Bonded Polymer Blends. Prog. Polym. Sci. 1995, 20, 1-59. 89 Coleman, M.M.; Painter, P.C. Prediction of the Phase Behaviour of Hydrogen-Bonded Polymer Blends. Aust. J. Chem. 2006, 59, 499-507.

22

bonding groups at the chain ends phase separate from the bulk polymer.90,91 This is

particularly possible when hydrogen bonding interactions take place in multiple directions,

facilitating the organization of the chain ends.92

2.3.1 Block Copolymers Involving Single Hydrogen Bonding Groups

Hydrogen bonding block copolymers containing single hydrogen bonding groups have

drawn attention due to the simplicity of their preparation via anionic polymerization

techniques of commonly available monomers. One specific template that has occupied

researchers is poly(vinylpyridine) which is often blended with complementary

poly(methacrylic acid)93 or poly(4-hydroxystyrene). Anionic polymerization possesses a

weakness in these cases due to the sensitivity of anionic polymerization to protic

functionality. Thus, protecting group strategies are often employed. In the case of

4-hydroxystyrene, silyl protecting groups are employed and in the case of methacrylic acid

residues, tert-butyl ester protecting groups are employed. Another strategy involves

post-polymerization modification. Liu and Jiang introduced carboxylic acid groups and

hydroxyl groups into SEBS polymers via Friedel-Crafts acylation and subsequent oxidation

90 Lillya, C. P.; Baker, R. J.; Huette, S.; Winter, H. H.; Lin, H.-G.; Shi, J.; Dickinson, L. C.; Chien, J. C. W. Linear Chain Extension through Associative Termini. Macromolecules 1992, 25, 2076-80. 91 Sivakova, S.; Bohnsak, D. A.; Mackay, M. E.; Suwanmala, P.; Rowan, S. J. Utilization of a Combination of Weak Hydrogen-Bonding Interactions and Phase Segregation to Yield Highly Thermosensitive Supramolecular Polymers. J Am Chem Soc 2005, 127, 18202-11. 92 Kautz, H.; van Beek, D. J. M.; Sijbesma, R. P.; Meijer, E. W. Cooperative End-to-End and Lateral Hydrogen-Bonding Motifs in Supramolecular Thermoplastic Elastomers. Macromolecules 2006, 39, 4265-7. 93 Jiang, S.; Gopfert, A.; Abetz, V. Novel Morphologies of Block Copolymer Blends via Hydrogen Bonding. Macromolecules 2003, 31, 6171-7.

23

or reduction of the ketone functional groups.94 Other strategies involve protecting group

chemistry. In the case of 4-hydroxystyrene blocks, a silyl protected monomer is polymerized

and deprotected after completion of the reaction.

Block copolymers containing complementary monomers such as 2-vinylpyridine and

4-hydroxystyrene or methacrylic acid were shown to produce novel morphologies in which

the complementary segments are mixed in domains which are phase separated from the bulk

polymer. 95 Abetz et al. blended poly(styrene-b-butadiene-b-tert-butyl

methacrylate-co-methacrylic acid) (SBT/A) with poly(styrene-b-2-vinylpyridine) (SV) to

obtain a compatibilized blend. The degree of hydrogen bonding interaction was varied

through controlling the level of hydrolysis of the tert-butyl methacrylate residues to

methacrylic acid residues. For partially hydrolyzed SBT polymers (18-51% hydrolyzed),

blending with SV led to a transition from a double gyroid or lamellar morphology

(SBT/A---A/TBS) to hcp V-T/A cylinders in B lamella alternating with S lamella.

Matsushita et al. carried out a similar study in which

poly(2-vinylpyridine-b-isoprene-b-2-vinylpyridine) triblocks with a mole fraction of

vinylpyridine of 0.07 and poly(styrene-b-4-hydroxystyrene) with 4-hydroxystyrene mole

fraction of 0.14 were blended in either a 1:1 or 2:1 2-vinylpyridine to 4-hydroxystyrene

94 Liu, L.; Jiang, M. Synthesis of Novel Triblock Copolymers Containing Hydrogen-Bond Interaction Groups via Chemical Modification of Hydrogenated Poly (styrene-block-butadiene-block-styrene). Macromolecules 1995, 28, 8702-4. 95 Asari, T.; Matsuo, S.; Takano, A.; Matsushita, Y. Three-Phase Hierarchical Structures from AB/CD Diblock Copolymer Blends with Complemental Hydrogen Bonding Interaction. Macromolecules 2005, 38, 8811-5.

24

ratio.96 Archimedean tile morphologies resulted which consisted of rows of vinylpyridine

with 4-hydroxystyrene cylinders staggered between isoprene and styrene lamella for the 1:1

ratio or hexagons of styrene in an isoprene matrix with 2-vinylpyridine with

4-hydroxystyrene cylinders at the corners of the styrene hexagons (Figure 2.2). Matsushita

et al. established the 4-hydroxystyrene / 2-vinylpyridine hydrogen bonding interaction from

1H NMR where a shifting of the OH proton was visible with the addition of vinylpyridine

containing copolymers.

96 Asari, T.; Arai, S.; Takano, A.; Matsushita, Y. Archimedean Tiling Structures from ABA/CD Block Copolymer Blends Having Intermolecular Association with Hydrogen Bonding. Macromolecules 2006, 39, 2232-7.

25

Figure 2.2. An Archimedean tile morphology for blends of

poly(2-vinylpyridine-b-isoprene-b-vinylpyridine) with poly(styrene-b-4-hydroxystyrene) in a

2:1 vinylpyridine to hydroxystyrene blend. The vinylpyridine/hydroxystyrene domains are

the cylinders at the vertices of polystyrene hexagons within a polyisoprene continuous phase.

Reprinted with permission from Asari et al.97 Copyright 2006, American Chemical Society.

97 Asari, T.; Arai, S.; Takano, A.; Matsushita, Y. Archimedean Tiling Structures from ABA/CD Block Copolymer Blends Having Intermolecular Association with Hydrogen Bonding. Macromolecules 2006, 39, 2232-7.

26

Painter and Coleman developed theoretical treatments to describe hydrogen bonding in

polymer blends.98,99 In general, the compatibilization of blends reduces the sizes of the

domains present and increases the mechanical properties while reducing melt viscosity, as

Huang et al. observed in studies of blending syndiotactic polystyrene with a thermoplastic

polyurethane using a poly(styrene-b-4-vinylpyridine) block copolymer.100 The reduction of

interfacial tension through the use of hydrogen bonding block copolymers is the primary

mechanism to improve blend miscibility. Blends of poly(2,5-dimethyl-1,4-phenylene oxide)

(PPO) and poly(ethylene-co-acrylic acid) were compatibilized using

poly(styrene-b-2-ethyl-2-oxazoline) due to the hydrogen bonding interactions of the amine

and the carboxylic acid and the compatibility of the polystyrene block with PPO.101 Tensile

strength and elongation of blends increased as domain size decreased with the addition of a

small amount (~5 wt%) of the poly(styrene-b-2-ethyl-2-oxazoline). Frechet and Kramer have

pursued living anionic and atom transfer radical polymerization (ATRP) of block and graft

copolymers of styrene and 4-hydroxystyrene for strengthening the interface between

polystyrene and poly(4-vinylpyridine). 102 The hydrogen bonding between the

98 Coleman, M. M.; Graf, J. F.; Painter, P. C., Specific Interactions and the Miscibility of Polymer Blends. Technomic: Lancaster, PA, 1991. 99 Painter, P. C.; Veytsman, B.; Kumar, S.; Shenoy, S.; Graf, J. F.; Xu, Y.; Coleman, M. M. Intramolecular Screening Effects in Polymer Mixtures. 1. Hydrogen-Bonded Polymer Blends. Macromolecules 1997, 30, 932-42. 100 Xu, S.; Chen, B.; Tang, T.; Huang, B. Syndiotactic polystyrene/thermoplastic polyurethane blends using poly(styrene-b-4-vinylpyridine) diblock copolymer as a compatibilizer. Polymer 1999, 40, 3399-406. 101 Xu, S.; Zhao, H.; Tang, T.; Dong, L.; Huang, B. Effect and mechanism in compatibilization of poly(styrene-b-2-ethyl-2-oxazoline) diblock copolymer in poly(2,6-dimethyl-1,4-phenylene oxide)/poly(ethylene-ran-acrylic acid) blends. Polymer 1999, 40, 1537-45. 102 Edgecombe, B. D.; Stein, J. A.; Frechet, J. M. J.; Xu, Z.; Kramer, E. J. The Role of Polymer Architecture in Strengthening Polymer-Polymer Interfaces: A Comparison of Graft, Block, and Random Copolymers Containing Hydrogen-Bonding Moieties. Macromolecules 1998, 31, 1292-304.

27

poly(4-hydroxystyrene) block and the poly(4-vinylpyridine) led to strong interactions which

allowed the use of poly(4-hydroxystyrene) blocks that were below the entanglement

molecular weight (Mc). In contrast, the polystyrene blocks possessed molecular weights

above Mc, which allowed some degree of entanglement with the polystyrene side of the

interface.

Often, self-association and multiple modes of association of hydrogen bonding groups

leads to complexity in the behavior of hydrogen bonded systems in which complementary

hydrogen bonding groups are involved. Kwei et al. synthesized

poly(styrene-b-vinylphenyldimethylsilanol) polymers via anionic polymerization of silane

(Si-H) containing monomers and subsequent post-polymerization oxidation with

dimethyldioxirane.103 The stronger acidity of the silanol group compared to the hydroxyl

group was expected to result in greater hydrogen bonding donating capabilities. However,

self-association of the silanol residues was found to play a large role in the behavior of these

copolymers. Block copolymers with a range of 11-33% conversion to silanol groups were

miscible with the weak hydrogen bond accepting homopolymer poly(n-butyl methacrylate)

whereas higher or lower conversions led to macrophase separation. Blends of the 21% silanol

block copolymer with the stronger hydrogen bond acceptor poly(4-vinylpyridine) or

poly(N-vinylpyrrolidone) formed clear films in all cases and exhibited hydrogen bonding

through changes in the FTIR spectrum.

103 Han, Y. K.; Pearce, E. M.; Kwei, T. K. Poly(styrene-b-vinylphenyldimethylsilanol) and Its Blends with Homopolymers. Macromolecules 2000, 33, 1321-9.

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2.3.2 Nucleobase Containing Hydrogen Bonding Block Copolymers

Nucleobase containing hydrogen bonding block copolymers are typically synthesized

via techniques which are amenable to protic functionality of the hydrogen bonding groups

such as living radical or methathesis polymerization techniques. Also, nucleobase functional

polymers are synthesized via post-polymerization techniques, although these are typically

hampered from incomplete conversion and side reactions. Nucleobase associations possess

strengths in the range of 100 M-1 (A-T, two hydrogen bonds) to 104 M-1 (C-G, three hydrogen

bonds) which places them between simple single hydrogen bonds and synthetic quadruple, or

higher multiple hydrogen bonding interactions.104,105 Recent computational studies on the

energy of hydrogen bonding interactions in DNA duplexes revealed values of ~14 kcal/mol

for the A-T pair and ~27 kcal/mol for the C-G pair.106 For adenine-uracil (A-U) hydrogen

bonds in chloroform, the association energy was determined experimentally from an

Arrhenius plot of association constants, yielding a value of 6.2 kcal/mol.107 Nucleobases are

complementary in nature, so that specific pairs such as adenine and thymine or uracil (A-T,

A-U) or cytosine and guanine (C-G) are typically employed. Rowan et al. noted that the

behavior of the isolated nucleobases in synthetic polymers is quite different from their

104 Kyogoku, Y.; Lord, R. C.; Rich, A. The Effect of Substituents on the Hydrogen Bonding of Adenine and Uracil Derivatives. Proc Natl Acad Sci USA 1967, 57, 250-7. 105 Thomas, G. J.; Kyogoku, Y. Hypochromism Accompanying Purine-Pyrimidine Association Interactions. J Am Chem Soc 1967, 89, 4170-5. 106 Sponer, J.; Jurecka, P.; Hobza, P. Accurate Interaction Energies of Hydrogen-Bonded Nucleic Acid Base Pairs. J. Am. Chem. Soc. 2004, 126, 10142-51. 107 Kyogoku, Y.; Lord, R. C.; Rich, A. An Infrared Study of Hydrogen Bonding between Adenine and Uracil Derivatives in Chloroform Solution. J Am Chem Soc 1967, 89, 496-504.

29

behavior in DNA where they bond to a complementary base.108 Multiple association modes

are also possible for these nucleobases, including the primary Watson-Crick mode which is

present in DNA and the less commonly observed Hoogsteen association mode,109 as well as

several self-association modes. The self-association modes of typical nucleobases are

extremely weak in nature and exhibit association constants less than 10 M-1.110 As in DNA,

other non-covalent interactions such as π-π stacking are often present with these heterocyclic

bases.

As for DNA, synthetic nucleobase containing polymers have exhibited a “melting” in

solution due to the unraveling of cooperatively associated chains. One must note, however,

that the structure of the associated species was not elucidated and likely possesses little

resemblance to the double helix of DNA. Lutz et al. observed this melting phenomenon in

mixtures of random copolymers of adenine and thymine functionalized styrenic monomers,

9-(4-vinylbenzyl)adenine and 1-(vinylbenzyl) thymine, with dodecylmethacrylate. 111 , 112

These copolymers organized in low-dielectric constant organic solvents (chloroform and

dioxane) at concentrations near 3 x 10-5 M-1. A decrease in the UV absorbance near 260 nm

for the complex compared to the individual copolymers suggesting the formation of stacked

108 Sivakova, S.; Bohnsak, D. A.; Mackay, M. E.; Suwanmala, P.; Rowan, S. J. Utilization of a Combination of Weak Hydrogen-Bonding Interactions and Phase Segregation to Yield Highly Thermosensitive Supramolecular Polymers. J Am Chem Soc 2005, 127, 18202-11. 109 Ghosal, G.; Muniyappa, K. Hoogsteen base-pairing revisited: Resolving a role in normal biological processes and human diseases. Biochemical and Biophysical Research Communications 2006, 343, 1-7. 110 Kyogoku, Y.; Lord, R. C.; Rich, A. The Effect of Substituents on the Hydrogen Bonding of Adenine and Uracil Derivatives. Proc Natl Acad Sci USA 1967, 57, 250-7. 111 Lutz, J. F.; Thunemann, A. F.; Rurack, K. DNA-like “Melting” of Adenine- and Thymine-Functionalized Synthetic Copolymers. Macromolecules 2005, 38, 8124-6. 112 Lutz, J. F.; Thunemann, A. F.; Nehring, R. Preparation by Controlled Radical Polymerization and Self-Assembly via Base-Recognition of Synthetic Polymers Bearing Complementary Nucleobases. J Polym Sci, Part A: Polym Chem 2005, 43, 4805-18.

30

nucleotide base pairs. The hypochromic effect, which is also observed in DNA, increased

with solution concentration due to a shift to a more associated state. The hypochromic

effect diminished with heating, as a result of thermal disruption of the hydrogen bonded

complex, and a characteristic “melting” temperature was measured at 325 K, much as in the

melting of A-T DNA oligonucleotides at 325 K.

Haddleton et al. reported on the use of ATRP for the synthesis of uridine and adenosine

functionalized methacrylate homopolymers as well as end-functionalization using uridine and

adenosine functional initiators.113 These uridine and adenonsine monomers consisted of the

nucleotide bases uracil and adenine connected to the five membered deoxyribose sugars

present in DNA, and subsequently bonded to methacrylate groups. In their study, silyl

protecting groups were employed on the hydroxyl groups of the uridine and adenosine

monomers to improve their solubility in organic solvents. Narrow polydispersities were

obtained, however, molecular weights of the hydrogen bonding homopolymers were typically

low (<10000 g/mol). Glass transition temperatures for the hydrogen bonding methacrylate

homopolymers, even at these low molecular weights were near 140 oC.

van Hest et al. synthesized nucleobase functional block copolymers containing thymine

via ATRP of a thymine methacrylate monomer from a PEG-macroinitiator.114 This polymer

was introduced into the polymerization of an adenine containing methacrylate monomer in

order to attempt to template the polymerization of the adenine containing monomer. Instead,

however, a rate enhancement of the adenine monomer polymerization reaction was observed.

113 Marsh, A.; Khan, A.; Haddleton, D. H.; Hannon, M. J. Atom Transfer Polymerization: Use of Uridine and Adenosine Derivatized Monomers and Initiators. Macromolecules 1999, 32, 8725-31. 114 Spijker, H. J.; Dirks, A. J.; van Hest, J. C. M. Unusual rate enhancement in the thymine assisted ATRP process of adenine monomers. Polymer 2005, 46, 8528-35.

31

Similar rate enhancements were observed with the addition of a thymine small molecule,

suggesting that competitive coordination of the adenine groups to the copper ATRP catalyst

occurred, which slowed reaction rates and was disrupted due to the hydrogen bonding

association to thymine.

Sleiman et al. have synthesized adenine functional block copolymers using

ring-opening methathesis polymerization (ROMP) of substituted oxonorbornene monomers

(Figure 2.3). 115 The adenine containing block copolymers self-assembled during

evaporation from dilute solutions into cylindrical shaped structures (Figure 2.4). The ability

to form these structures was attributed to the ability of adenine to hydrogen bond in two

directions with neighboring adenine molecules. Apparently, low degrees of crystallinity in

the adenine homopolymers were observed from WAXS and DSC. Novel, non-covalent

protecting chemistry involving addition of complementary succinimide was utilized to

improve the conversion of the adenine containing monomer.

Inaki, who has synthesized a wide range of nucleobase functionalized random and

homopolymers,116 has also synthesized block copolymers containing thymine and uracil

groups in the main chain, through ring-opening cationic and anionic polymerization of cyclic

derivatives of the nucleobases.117

115 Bazzi, H.; Sleiman, H. Adenine-Containing Block Copolymers via Ring-Opening Metathesis Polymerization: Synthesis and Self-Assembly into Rod Morphologies. Macromolecules 2002, 35, 9617-20. 116 Inaki, Y. Synthetic Nucleic Acid Analogs. Prog Polym Sci 1992, 17, 515-70. 117 Inaki, Y.; Futagawa, H.; Takemoto, K. Polymerization of cyclic derivatives of uracil and thymine. J Polym Sci, Polym Chem Ed 1980, 18, 2959-69.

32

Figure 2.3. Synthesis of adenine containing block copolymers via a ROMP methodology.

Reprinted with permission from Bazzi and Sleiman118 Copyright 2002 American Chemical

Society.

118 Bazzi, H.; Sleiman, H. Adenine-Containing Block Copolymers via Ring-Opening Metathesis Polymerization: Synthesis and Self-Assembly into Rod Morphologies. Macromolecules 2002, 35, 9617-20.

33

Figure 2.4. Formation of cylindrical aggregates via multi-directional self-association bonding

of adenine functional block copolymers. Reprinted with permission from Bazzi and

Sleiman119 Copyright 2005, American Chemical Society.

119 Bazzi, H.; Sleiman, H. Adenine-Containing Block Copolymers via Ring-Opening Metathesis Polymerization: Synthesis and Self-Assembly into Rod Morphologies. Macromolecules 2002, 35, 9617-20.

34

Hydrogen bonding in nucleobase functionalized block copolymers was utilized to

template nanostructured materials in solution for potential drug delivery applications. In

work from Liu et al., crosslinkable and hydrogen bonding functionality were introduced in

the form of poly(2-cinnamoyloxyethyl methacrylate-co-2-thyminylacetoxyethyl

methacrylate-b-tert-butyl acrylate). Complementary, non-crosslinkable

poly(2-hydrocinnamoyloxyethyl methacrylate-co-9-adeninylacetoxyethyl methacrylate) was

also synthesized. These complementary polymers were solution blended in

chloroform/cyclohexane mixtures to produce micelles containing the nucleotide pairs with

soluble tert-butyl acrylate blocks extending into solution.120 Photocrosslinking of these

micelles and subsequent extraction of the adenine functionalized polymers resulted in porous

nanospheres, which absorbed adenine from solution more rapidly than non-extracted or

non-crosslinked micelles. Kinetics varying from first order for low molar mass porogens to

zero order for higher molar mass porogens were observed, which suggested potential

applications in drug delivery.121 In a related study, Hu and Liu produced mixed micelles

from poly(2-cinnamoyloxyethyl methacrylate-co-2-thyminylacetoxyethyl

methacrylate-b-tert-butyl acrylate) and poly(2-cinnamoyloxyethyl

methacrylate-co-9-adeninylacetoxyethyl methacrylate-b-styrene). 122 , 123 These mixed

micelles were photocrosslinked and then the tert-butyl acrylate blocks were hydrolyzed to

120 Zhou, J.; Li, Z.; Liu, G. Diblock Copolymer Nanospheres with Porous Cores. Macromolecules 2002, 35, 3690-6. 121 Liu, G.; Zhou, J. First- and Zero-Order Kinetics of Porogen Release from the Cross-Linked Cores of Diblock Nanospheres. Macromolecules 2003, 36, 5279-84. 122 Hu, J.; Lui, G. Chain Mixing and Segregation in B-C and C-D Diblock Copolymer Micelles. Macromolecules 2005, 38, 8058-65. 123 Yan, X.; Liu, G.; Hu, J.; Willson, C. G. Coaggregation of B-C and D-C Diblock Copolymers with H-Bonding C Blocks in Block-Selective Solvents. Macromolecules 2006, 39, 1906-12.

35

produce poly(acrylic acid) residues, which phase separated from the styrene functionalized

block copolymer tails in the micellar corona, as observed in TEM. The phase separation

resulted in either two-faced appearance or flower-like patterns in the corona.

Lehn and Rotello’s groups extensively studied diacyldiaminopyridines which form

triple hydrogen bonded associated structures with uracil and thymine groups.124125126

-127 Rotello

et al. studied the formation of vesicles from mixtures of randomly functionalized

complementary copolymers containing thymine groups and another with

diacyldiaminopyridine units.128 The complementary flavin guest molecule was incorporated

into the ~ 3 μm spherical vesicles. Bis(thymine) functional small molecules served as

non-covalent crosslinkers when mixed with randomly functionalized diacyldiaminopyridine

functionalized polystyrene.129 In chloroform solution, mixing of these complementary units

led to the formation of ~ 1 μm microgels. Temperature dependent turbidity measurements at

700 nm showed that clearing of the solutions was obtained upon heating to 50 oC due to

thermal disruption of hydrogen bonding and turbidity was reproducibly obtained upon

124 Gulik-Krzywicki, T.; Fouquey, C.; Lehn, J. M. Electron microscopic study of supramolecular liquid crystalline polymers formed by molecular-recognition-directed self-assembly from complementary chiral components. Proc. Natl. Acad. Sci. USA 1993, 90, 163-7. 125 Sanyal, A.; Norsten, T. B.; Uzun, O.; Rotello, V. M. Adsorption/Desorption of Mono- and Diblock Copolymers on Surfaces Using Specific Hydrogen Bonding Interactions. Langmuir 2004, 20, 5958-64. 126 Stubbs, L. P.; Weck, M. Towards a Universal Polymer Backbone: Design and Synthesis of Polymeric Scaffolds Containing Terminal Hydrogen-Bonding Recognition Motifs at Each Repeating Unit. Chem Eur J 2003, 9, 992-9. 127 Carroll, J. B.; Waddon, A. J.; Nakade, H.; Rotello, V. M. “Plug and Play” Polymers. Thermal and X-ray Characterizations of Noncovalently Grafted Polyhedral Oligomeric Silsesquioxane (POSS)-Polystyrene Nanocomposites. Macromolecules 2003, 36, 6289-91. 128 Ilhan, F.; Galow, T. H.; Gray, M.; Clavier, G.; Rotello, V. M. Giant Vesicle Formation through Self-Assembly of Complementary Random Copolymers. J Am Chem Soc 2000, 122, 5895-6. 129 Thibault, R. J.; Hotchkiss, P. J.; Gray, M.; Rotello, V. M. Thermally Reversible Formation of Microspheres through Non-Covalent Polymer Cross-Linking. J Am Chem Soc 2003, 125, 11249-52.

36

cooling back to room temperature. Rotello has further demonstrated reversible attachment of

diacyldiaminopyridine containing styrenic copolymers to thymine modified surfaces using

XPS and quartz crystal microbalances to measure the adsorption. The adsorbed polymer was

easily removed via washing with hydrogen bond screening solvents such as

chloroform/ethanol mixtures but was retained upon washing with chloroform. 130

Non-covalent attachment of diacyldiaminopyridine functionalized polyoligosilsequioxanes

(POSS) to thymine functionalized polystyrene was also studied.131 Stubbs and Weck also

examined ROMP homopolymers of diacyldiaminopyridine and diacyldiaminotriazine

functionalized norbornenes.132 Due to the propensity for self-association of these hydrogen

bonding units, homopolymers precipitated from solution during polymerization. The

polymers were re-dissolved slowly through the addition of 1-butylthymine in chloroform. To

avoid precipitation during polymerization, the authors utilized non-covalent protecting

chemistry with the addition of 1-butylthymine.

Block copolymers containing the diacyldiaminopyridine group were also synthesized.

Starting with poly(tert-butyl acrylate-b-hydroxyethylmethacrylate), block copolymers

synthesized from ATRP, Li et al. carried out post-polymerization esterification of the

hydroxyl groups with a carboxylic acid containing acrylamide functionalized

130 Sanyal, A.; Norsten, T. B.; Uzun, O.; Rotello, V. M. Adsorption/Desorption of Mono- and Diblock Copolymers on Surfaces Using Specific Hydrogen Bonding Interactions. Langmuir 2004, 20, 5958-64. 131 Carroll, J. B.; Waddon, A. J.; Nakade, H.; Rotello, V. M. “Plug and Play” Polymers. Thermal and X-ray Characterizations of Noncovalently Grafted Polyhedral Oligomeric Silsesquioxane (POSS)-Polystyrene Nanocomposites. Macromolecules 2003, 36, 6289-91. 132 Stubbs, L. P.; Weck, M. Towards a Universal Polymer Backbone: Design and Synthesis of Polymeric Scaffolds Containing Terminal Hydrogen-Bonding Recognition Motifs at Each Repeating Unit. Chem Eur J 2003, 9, 992-9.

37

diacyldiaminopyridine hydrogen bonding crosslinker.133 The unreacted hydroxyl groups

were then reacted with methacrylic anhydride to introduce further crosslinkable groups. The

block copolymers hydrogen bonded with alkyl functional thymines and uracils in

non-selective solvents as observed in FTIR spectra. The introduction of a selective solvent

(cyclohexane) produced micelles which were then crosslinked in solution. Extraction of the

alkyl functional thymines or uracils through dialysis led to hollow nanospheres. Binding

isotherms of the nanospheres with the thymine or uracil containing molecules were obtained.

2.3.3 Block Copolymers Containing DNA Oligonucleotides

Conjugates of synthetic polymers with DNA oligonucleotides were also synthesized.

Matsushita et al. utilized the phosphoramidite route to incorporate nucleotide bases in a

stepwise fashion from a hydroxyl containing polymer precursor.134 Coupling of thymidine

phosphoramidite to polymeric hydroxyl groups was achieved with benzimidazoleum triflate

(Figure 2.5). Oxidation with tert-butyl hydroperoxide led to the formation of phosphodiester

bonds. The addition of acid allowed deprotection of the remaining hydroxyl groups of the

deoxyribose sugar linkage, enabling repetition of the chemistry to generate multiple

thymidine residues. Matsushita et al. synthesized anionic deuterated polystyrenes with five

terminal thymidine units which formed a cylindrical morphology. Microphase separation was

also visible for a single terminal thymidine unit.

133 Li, Z.; Ding, J.; Day, M.; Tao, Y. Molecularly Imprinted Polymeric Nanospheres by Diblock Copolymer Self-Assembly. Macromolecules 2006, 39, 2629-36. 134 Noro, A.; Nagata, Y.; Tsukamoto, M.; Hayakawa, Y.; Takano, A.; Matsushita, Y. Novel Synthesis and Characterization of Bioconjugate Block Copolymers Having Oligonucleotides. Biomacromolecules 2005, 6, 2328-33.

38

Figure 2.5. Scheme for stepwise synthesis of oligonucleotides via coupling of

phosphoramidite functionalized nucleosides. Reprinted with permission from Noro et al.135

Copright 2005, American Chemical Society.

135 Noro, A.; Nagata, Y.; Tsukamoto, M.; Hayakawa, Y.; Takano, A.; Matsushita, Y. Novel Synthesis and Characterization of Bioconjugate Block Copolymers Having Oligonucleotides. Biomacromolecules 2005, 6, 2328-33.

39

In work from Craig et al., DNA oligonucleotides were synthesized consisting of 8-base

self-complementary sequences repeated twice in the same molecule to create ditopic linear

self assembly.136 The association of these molecules resulted in a degree of polymerization

of roughly 10, corresponding to a molecular weight of 182000 g/mol at 0.54 mM

concentration in water. Injections of varying volumes of the associated polymer onto a size

exclusion chromatograph resulted in decreasing apparent molecular weight for smaller

injection volumes, which was consistent with dilution leading to a lower effective molecular

weight. The solution viscosity exhibited a slope discontinuity from 1.8 to 3.7, indicating a

transition from dilute to semi-dilute unentangled behavior, which is characteristic of high

molecular weight polymers. The radius of gyration (Rg) of the associated structures scaled

with Mw0.7, indicating rod-like behavior typical of DNA. The introduction of flexible PEG

spacers between the self-complementary 8-base sequences led to the formation of associated

cyclic structures and slow reorganization into linear, high molecular weight species.

Watson et al. synthesized ROMP homopolymers and block copolymers from hydroxyl

containing norbornene monomers. 137 The hydroxyl functional groups were

phosphoramidated and attached to DNA oligonucleotides. Complementary DNA

oligonucleotide containing ROMP polymers were mixed in solution resulted in precipitation

of the hydrogen bonded complex. Heating of this complex produced a melting point similar

to that observed in pure DNA oligonucleotides near 75 oC. Gold nanoparticles containing

DNA strands were complexed with complementary difunctional polymeric oligonucleotides,

136 Xu, J.; Fogleman, E. A.; Craig, S. L. Structure and Properties of DNA-Based Reversible Polymers. Macromolecules 2004, 37, 1863-70. 137 Watson, K. J.; Park, S. J.; Im, J. H.; Nguyen, S. B. T.; Mirkin, C. A. DNA-Block Copolymer Conjugates. J Am Chem Soc 2001, 123, 5592-3.

40

resulting in aggregation of the gold nanoparticles into a network structure as observed with

TEM and surface plasmon resonance.

Peptide nucleic acids (PNAs) are a class of polymers with peptide or pseudopeptide

backbones and pendant nucleotide bases. PNAs typically lack the helicity of DNA but benefit

from stronger association and solubility in organic solvents. Berry et al. polymerized

hydroxyethylacrylate from a bromo functional PNA hexamer via ATRP. 138 This

poly(hydroxyethyl acrylate-b-PNA) associated with a PNA with three complementary arms,

resulting in an apparent molecular weight three times higher than the precursor. Solution

phase “melting” of these PNA assemblies occurred at 30 oC. Biologically inspired hydrogen

bonding block copolymers containing peptide sequences139 or polysaccharide140 blocks were

also studied recently. Klok et al. studied the synthesis of poly(styrene-b-γ-benzyl-L-glutamate)

copolymers.141

2.3.4 Block Copolymers Containing other Hydrogen Bonding Arrays

Sleiman’s group also studied hydrogen bonding ROMP block copolymers containing

dicarboximide hydrogen bonding groups as the polar, hydrogen bonding block and alkylated

138 Wang, Y.; Armitage, B. A.; Berry, G. C. Reversible Association of PNA-Terminated Poly(2-hydroxyethyl acrylate) from ATRP. Macromolecules 2005, 38, 5846-8. 139 Arimura, H.; Ohya, Y.; Ouchi, T. Formation of Core-Shell Type Biodegradable Polymeric Micelles from Amphiphilic Poly(aspartic acid)-block-Polylactide Diblock Copolymer. Biomacromolecules 2005, 6, 720-5. 140 Bosker, W. T. E.; Agoston, K.; Cohen Stuart, M. A.; Norde, W.; Timmermans, J. W.; Slaghek, T. M. Synthesis and Interfacial Behavior of Polystyrene-Polysaccharide Diblock Copolymers. Macromolecules 2003, 36, 1982-7. 141 Klok, H. A.; Langenwalter, J. F.; Lecommandoux, S. Self-Assembly of Peptide-Based Diblock Oligomers. Macromolecules 2000, 33, 7819-26.

41

dicarboximide residues as a hydrophobic block.142 Upon addition of water to a THF

solution of the block copolymers, large (100-300 nm) spherical aggregates formed which

were stained with CsOH, which deprotonated the dicarboximide groups. These polymers are

capable of hydrogen bonding with adenine due to the similarity of the dicarboximide group to

thymine and uracil. In another paper, Sleiman described the ROMP of ABC and BAC

triblock copolymers containing dicarboximide groups (A) and complementary

diacyldiaminopyridine groups (C) as well as a blocked, alkylated dicarboximide monomer

(B). The placement of the complementary groups on opposite ends of the block copolymer

(ABC) resulted in large aggregates in chloroform solution as well as micelles, while

placement of these complementary blocks adjacent to one another did not result in aggregate

formation, suggesting a tendency toward intramolecular association.143

Rotello et al. studied diaminotriazine randomly functionalized polystyrenes, which

exhibited strong intramolecular self-association leading to five-fold decreased radius of

gyration (Rg) values compared to nonfunctional polystyrenes in low polarity solvents such as

chloroform.144 The absence of acyl groups on diaminotriazine led to stronger self-association

and open more modes of self-association due to the presence of additional N-H protons.

The self-association of the diaminotriazine functional polymers led to lower association

constants with complementary flavin guests. Through a study of the temperature dependence

142 Dalphond, J.; Bazzi, H.; Kahrim, K.; Sleiman, H. Synthesis and Self-Assembly of Polymers Containing Dicarboximide Groups by Living Ring-Opening Metathesis Polymerization. Macromol Chem Phys 2002, 203, 1988-94. 143 Bazzi, H.; Bouffard, J.; Sleiman, H. Self-Complementary ABC Triblock Copolymers via Ring-Opening Metathesis Polymerization. Macromolecules 2003, 36, 7899-902. 144 Deans, R.; Ilhan, F.; Rotello, V. M. Recognition-Mediated Unfolding of a Self-Assembled Polymeric Globule. Macromolecules 1999, 32, 4956-60.

42

of the association constants between polymeric diaminotriazine and flavin as well as

monomeric diaminotriazine and flavin, entropic and enthalpic thermodynamic parameters

were deduced for the polymer unfolding process required to allow the association with flavin.

Based on comparing the enthalpy of unfolding (-4.66 kcal/mol) with that of association (7.00

kcal/mol), it was proposed that two hydrogen bonds were involved in the self-associated

folded chain while three were involved in the associated complex.

2.3.5 Order-Disorder Transitions (ODT) in Hydrogen Bonding Block Copolymers

Order-disorder transitions occur when a phase separated block copolymer melt is heated

to the point that the phase separated domains begin mixing. In block copolymers containing

hydrogen bonding functionality, hydrogen bonding interactions often control miscibility.

Thus the thermoreversibility of the hydrogen bonding interactions plays a role in the ODT.

Wang et al. studied order-disorder transitions in hydrogen bonding hydroxyl functionalized

diblock dendrons. In their work, poly(benzyl ether) and poly(ester) containing dendrons were

coupled and peripheral hydroxyl groups on the poly(ester) dendron were subsequently

deprotected. SAXS indicated a lamellar morphology which disordered at 50 oC, which

corresponded to transition from bound to free hydroxyl absorbances in FTIR

measurements.145

145 Yuan, F.; Wang, W.; Yang, M.; Zhang, X.; Li, J.; Li, H.; He, B.; Minch, B.; Lieser, G.; Wegner, G. Layered Structure and Order-to-Disorder Transition in a Block Codendrimer Caused by Intermolecular Hydrogen Bonds. Macromolecules 2006, 39, 3982-5.

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Lee and Han studied low molecular weight poly(styrene-b-isoprene) diblocks

synthesized anionically in THF.146 The high 1,2- and 3,4- enchainment produced from the

polar polymerization solvent resulted in the absence of microphase separation between the

blocks. Upon hydroboration-oxidation of the isoprene double bonds, hydroxyl groups were

selectively introduced to the isoprene units and microphase separation was obtained. An

order-disorder transition temperature near 195 oC was obtained for a

poly(styrene-b-hydroxylated isoprene) with block molecular weights of 14K-3K, and the

ODT was much higher for longer hydroxylated isoprene blocks. In-situ FTIR indicated the

loss of hydrogen bonds between hydroxyl groups near the ODT that was measured using melt

rheology.

2.4 Telechelic Hydrogen Bond Functional Polymers

Telechelic hydrogen bonding is a second method of obtaining localized hydrogen

bonding functionality. Although the ability to increase the association strength via

cooperative hydrogen bonding of neighboring groups is sacrificed, more well-defined

supramolecular structures are attainable. The effect of telechelic hydrogen bonding groups

diminishes with increasing molecular weight, however, in low molecular weight systems

even weak hydrogen bonding groups lead to significant changes in properties.147 Recently,

attention has centered on strong telechelic hydrogen bonding, since the degree of association

146 Lee, K. M.; Han, C. D. Order-Disorder Transition Induced by the Hydroxylation of Homogeneous Polystyrene-block-polyisoprene Copolymer. Macromolecules 2002, 35, 760-9. 147 Lillya, C. P.; Baker, R. J.; Huette, S.; Winter, H. H.; Lin, H.-G.; Shi, J.; Dickinson, L. C.; Chien, J. C. W. Linear Chain Extension through Associative Termini. Macromolecules 1992, 25, 2076-80.

44

of telechelic polymers depends on the association constant raised to the one-half power.148

Meijer149150

-151 and Long152,153 have extensively studied the self-complementary quadruple

hydrogen bonding unit 2-uriedo-4[1H]-pyrimidone (UPy). This DDAA quadruple hydrogen

array forms very strong self-associated dimers in solution, with association constants near 6 x

107 M-1 in chloroform and dimer lifetimes of 170 ms in chloroform. 154 Telechelic

functionalization of molecules with UPy was shown to result in the formation of hydrogen

bonded extended chain structures where the degree of polymerization (as determined from

solution viscosity) depended on the solution concentration.155 Much like a step-growth

condensation polymerization, this leads to sensitivity of the non-covalent degree of

polymerization on monofunctional end-cappers and the formation of cycles are observed in

cases where the spacer between the UPy groups is bent.

148 Xu, J.; Fogleman, E. A.; Craig, S. L. Structure and Properties of DNA-Based Reversible Polymers. Macromolecules 2004, 37, 1863-70. 149 Brunsveld, L.; Folmer, B. J. B.; Meijer, E. W.; Sijbesma, R. P. Supramolecular Polymers. Chem Rev 2001, 101, 4071-98. 150 Ligthart, G. B. W. L.; Ohkawa, H.; Sijbesma, R. P.; Meijer, E. W. Complementary Quadruple Hydrogen Bonding in Supramolecular Copolymers. J Am Chem Soc 2005, 127, 810-11. 151 Hirschberg, J. H. K. K.; Beijer, F. H.; van Aert, H. A.; Magusin, P. C. M. M.; Sijbesma, R. P.; Meijer, E. W. Supramolecular Polymers from Linear Telechelic Siloxanes with Quadruple-Hydrogen-Bonded Units. Macromolecules 1999, 32, 2696-705. 152 Yamauchi, K.; Lizotte, J. R.; Hercules, D. M.; Vergne, M. J.; Long, T. E. Combinations of Microphase Separation and Terminal Multiple Hydrogen Bonding in Novel Macromolecules. J Am Chem Soc 2002, 124, 8599-604. 153 McKee, M. G.; Elkins, C.; Long, T. E. Influence of self-complementary hydrogen bonding on solution rheology/electrospinning relationships. Polymer 2004, 45, 8705-15 154 Söntjens, S. H. M.; Sijbesma, R. P.; van Genderen, M. H. P.; Meijer, E. W. Stability and Lifetime of Quadruply Hydrogen Bonded 2-Ureido-4[1H]-pyrimidinone Dimers. J Am Chem Soc 2000, 122, 7487-93. 155 Sijbesma, R. P.; Beijer, F. H.; Brunsveld, L.; Folmer, B. J. B.; Hirschberg, J. H. K. K.; Lange, R. F. M.; Lowe, J. K. L.; Meijer, E. W. Reversible Polymers Formed from Self-Complementary Monomers Using Quadruple Hydrogen Bonding. Science 1997, 278, 1601-4.

45

Some of the earliest telechelic UPy containing polymers were based on oligomeric (DP

= 2, 100) poly(dimethylsiloxane).156 The degrees of association observed through melt

rheological measurements ranged from 100 to 20 and decreased with increasing molecular

weight. The activation energy also decreased with increasing molecular weight and was

lower for a benzyl protected precursor (37 kJ/mol). A rubbery plateau was observed in melt

rheological experiments for the short (DP = 2) telechelic polymer, indicating entanglements

in the melt and associated structures with molecular weight above Mc. Solution rheological

measurements indicated that solution viscosity scaled with concentration to the 3.9, whereas a

benzyl protected analogue produced a scaling value of 1.06 (Figure 2.6). The higher exponent

for the hydrogen bonded compound was consistent with the Cates model for concentration

dependent association.157

156 Hirschberg, J. H. K. K.; Beijer, F. H.; van Aert, H. A.; Magusin, P. C. M. M.; Sijbesma, R. P.; Meijer, E. W. Supramolecular Polymers from Linear Telechelic Siloxanes with Quadruple-Hydrogen-Bonded Units. Macromolecules 1999, 32, 2696-705. 157 Cates, M. E. Reptation of living polymers: dynamics of entangled polymers in the presence of reversible chain-scission reactions. Macromolecules 1987, 20, 2289-96.

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Figure 2.6. Solution viscosity of (a) telechelic UPy functional PDMS and (b) benzyl

protected analog in chloroform at 20 oC. Reprinted with permission from Hirschberg et al.158

Copyright 1999, American Chemical Society.

158 Hirschberg, J. H. K. K.; Beijer, F. H.; van Aert, H. A.; Magusin, P. C. M. M.; Sijbesma, R. P.; Meijer, E. W. Supramolecular Polymers from Linear Telechelic Siloxanes with Quadruple-Hydrogen-Bonded Units. Macromolecules 1999, 32, 2696-705.

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Meijer et al. functionalized poly(ethylene oxide-co-propylene oxide) three-arm star

oligomers of Mn = 6000 g/mol (2000 g/mol arms) with UPy and urethane hydrogen bonding

groups.159 Due to the presence of three terminal UPy units, non-covalent networks could

form. Thus, the authors observed the formation of elastic solids from the viscous liquid

precursors, as well as increased solution viscosity in chloroform with increased concentration

dependence due to the concentration dependence of the hydrogen bonding association. In

melt rheological studies, plateaus in the storage modulus were observed, which were not

present in the oligomeric precursor and resembled those expected for high molecular weight

polymers. A urea-terminated analog exhibited a higher plateau modulus than the UPy

containing polymer, which was attributed to the formation of stacked arrays of hydrogen

bonding groups instead of simple dimers. In contrast, a covalent polyurethane network

prepared with the same oligomeric precursor exhibited a lower plateau modulus than the UPy

functional oligomers, which was attributed to the formation of a more thermodynamically

perfect network for the UPy polymer, due to the reversibility of the hydrogen bonding

interactions in comparison to the irreversible covalent bonds.

Due to the fact that the UPy group preferentially associates into dimers in both the

solution and solid state, the introduction of only two telechelic UPy groups leads to increased

effective molecular weight, without evidence of phase separation or elastic character for

low-Tg precursor. In recent work, Meijer et al. have placed urea and urethane groups

159 Lange, R. F. M.; van Gurp, M.; Meijer, E. W. Hydrogen-bonded supramolecular polymer networks. J. Polym. Sci. Part A. Polym. Chem. 1999, 37, 3657-70.

48

adjacent to telechelic UPy group, resulting in elastic behavior due to phase separation.160

These urethane and urea groups were responsible for lateral stacking of the chain ends, much

like that Wilkes et al. observed in model single hard segment polyurethanes and

polyureas.161,162 The lateral stacking of these telechelic hydrogen bonding groups gives rise

to fibril-like structures in surface morphology as observed from AFM, and more pronounced

stacking is observed for the stronger hydrogen bonding urea functional copolymers. The

presence of the UPy group increased the strain at break four-fold compared to simple

telechelic urea functionality due to the non-covalent chain extension and effectively more

difficult chain pullout from the hydrogen bonded fibrils.

Li et al. have synthesized napthyridine (Napy) complementary hydrogen bonding arrays

for UPy.163 These Napy groups associate to one particular tautomer of UPy with Ka values

near those of the UPy homodimerization (5 x 106 M-1) (Figure 2.7). Solution rheological

studies involving mixtures of bis(UPy) and bis(Napy) low molar mass compounds indicated

that solution viscosity remained high as the bis(Napy) was added to the bis(UPy), until more

than one equivalent was added, upon which time the solution viscosity decreased. 164

160 Kautz, H.; van Beek, D. J. M.; Sijbesma, R. P.; Meijer, E. W. Cooperative End-to-End and Lateral Hydrogen-Bonding Motifs in Supramolecular Thermoplastic Elastomers. Macromolecules 2006, 39, 4265-7. 161 Sheth, J. P.; Wilkes, G. L.; Fornof, A. R.; Long, T. E.; Yilgor, I. Probing the Hard Segment Phase Connectivity and Percolation in Model Segmented Poly(urethane urea) Copolymers. Macromolecules 2005, 38, 5681-5. 162 Sheth, J. P.; Klinedinst, D. B.; Wilkes, G. L.; Yilgor, E.; Yilgor, I. Role of chain symmetry and hydrogen bonding in segmented copolymers with monodisperse hard segments. Polymer 2005, 46, 7317-22. 163 Li, X. Q. K.; Jiang, X.; Wang, X. Z.; Li, Z. T. Novel multiply hydrogen-bonded heterodimers based on heterocyclic ureas. Folding and stability. Tetrahedron 2004, 60, 2063-9. 164 Ligthart, G. B. W. L.; Ohkawa, H.; Sijbesma, R. P.; Meijer, E. W. Complementary Quadruple Hydrogen Bonding in Supramolecular Copolymers. J Am Chem Soc 2005, 127, 810-11.

49

Recently, Meijer et al. functionalized a semicrystalline polyoctenamer synthesized using

ROMP with telechelic Napy functionality, and blended it with telechelic UPy functionalized

poly(ethylene-co-propylene).165 This resulted in the microphase separated structures via

AFM, whereas mixtures of non-functional analogs resulted in macrophase separation. Thus,

hydrogen bonding was utilized to effectively connect the blocks of a multiblock polymer.

165 Scherman, O. A.; Ligthart, G. B. W. L.; Ohkawa, H.; Sijbesma, R. P.; Meijer, E. W. Olefin metathesis and quadruple hydrogen bonding: A powerful combination in multistep supramolecular synthesis. Proc Natl Acad Sci USA 2006, 103, 11850-5.

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Figure 2.7. UPy homodimer (left) and heterodimer (right) with Napy via tautomerization.

Reprinted from Scherman et al.166 Copyright 2006 with permission from the National

Academy of Sciences, U.S.A.

166 Scherman, O. A.; Ligthart, G. B. W. L.; Ohkawa, H.; Sijbesma, R. P.; Meijer, E. W. Olefin metathesis and quadruple hydrogen bonding: A powerful combination in multistep supramolecular synthesis. Proc Natl Acad Sci USA 2006, 103, 11850-5.

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Long et al. studied the end-functionalization of polystyrene, polyisoprene and

poly(isoprene-b-styrene) with UPy groups.167 The introduction of the hydrogen bonding

groups lead to increased Tg and melt viscosities, with a decrease in melt viscosity at 80 oC,

which was attributed to hydrogen bonding dissociation. Long et al. also studied the terminal

functionalization of star-shaped and linear poly(ethylene-co-propylene)s.168 This resulted in

dramatic increases in melt viscosity, particularly in the case of the star-shaped polymer, and a

shift of the terminal region to longer times. Recently, Long et al. telechelically

end-functionalized poly(ester)s with UPy via post-polymerization reaction with an isocyanate

containing UPy. 169 Melt rheological analysis indicated higher viscosity for the UPy

containing polymer with a dramatic decrease near 80 oC to levels comparable to a

nonfunctional analog. Tensile strength and elongation of the UPy containing polyester

matched those of a nonfunctional polyester with twice the molecular weight, however, melt

viscosity was lower than for this high molecular weight polyester.

Telechelic nucleobase functional polymers have also gathered attention recently. Long

et al. has synthesized complementary nucleobase (thymine, adenine and purine)

end-functional polystyrenes via Michael addition to terminal acrylate groups, introduced via

167 Yamauchi, K.; Lizotte, J. R.; Hercules, D. M.; Vergne, M. J.; Long, T. E. Combinations of Microphase Separation and Terminal Multiple Hydrogen Bonding in Novel Macromolecules. J Am Chem Soc 2002, 124, 8599-604. 168 Elkins, C.; Viswanathan, K.; Long, T. E. Synthesis and Characterization of Star-Shaped Poly(ethylene-co-propylene) Polymers Bearing Terminal Self-Complementary Multiple Hydrogen-Bonding Sites. Macromolecules 2006, 39, 3132-9. 169 Yamauchi, K.; Kanomata, A.; Inoue, T.; Long, T. E. Thermoreversible Polyesters Consisting of Multiple Hydrogen Bonding (MHB). Macromolecules 2004, 37, 3519-22.

52

post-functionalization of anionic hydroxyl terminated polystyrene.170 The hydrogen bonding

groups were found to associate via 1H NMR studies, in which chemical shift changes of

hydrogen bonded protons were found to diminish on heating to 95 oC, indicating

thermoreversible association. Rowan et al. functionalized poly(tetramethylene oxide) with

acylated adenine and cytosine nucleobases.171 The film forming, solid-like properties of the

films were attributed to the weak self-association of the adenine and cytosine groups (< 5

M-1), in concert with phase separation, which increased the hydrogen bonding association via

concentration of the hydrogen bonding units. Rheological and x-ray scattering data studies on

the adenine functionalized polymer indicated the formation of stacks of the benzyl protected

adenine units showing the presence of π-stacking, which diminished on heating above 70 oC.

Blockage of the hydrogen bonding properties via alkyl substitution at the hydrogen bonding

(NH) protons resulted in reversion of the functional polymer to a liquid state. The protected

cytosine containing polymers did not exhibit π-stacking interactions, likely due to the bulky

aliphatic tert-butyl containing acyl group, but exhibited gel-like behavior in rheological

studies.

Binder et al. compatibilized blends of polyisobutylene and a bisphenol A containing

poly(ether ketone) using telechelic complementary hydrogen bonding.172 First, a thymine

and diaminopyridine hydrogen bonding pair with an association constant near 800 M-1 was

170 Yamauchi, K.; Lizotte, J. R.; Long, T. E. Synthesis and Characterization of Novel Complementary Multiple-Hydrogen Bonded (CMHB) Macromolecules via a Michael Addition. Macromolecules 2002, 35, 8745-50. 171 Sivakova, S.; Bohnsak, D. A.; Mackay, M. E.; Suwanmala, P.; Rowan, S. J. Utilization of a Combination of Weak Hydrogen-Bonding Interactions and Phase Segregation to Yield Highly Thermosensitive Supramolecular Polymers. J Am Chem Soc 2005, 127, 18202-11. 172 Binder, W. H.; Bernstorff, S.; Kluger, C.; Petraru, L.; Kunz, M. J. Tunable Materials from Hydrogen-Bonded Pseudo Block Copolymers. Adv Mater 2005, 17, 2824-8.

53

employed. This resulted in microphase separation as observed from TEM and SAXS. From

variable temperature SAXS studies, the blend was stable up to 250 oC, at which point the

poly(ether ketone) phase reached Tg and macrophase separation occurred. A stronger Janus

wedge and barbituric acid hydrogen bonding pair with an association constant near 104 - 106

M-1 resulted in stability of the blend to nearly 80 oC above the poly(ether ketone) glass

transition.

Craig and coworkers developed a calixarene with four terminal urea groups in a radial,

cone-shaped geometry (Figure 2.8).173 The self-complementarity of this hydrogen bonding

calixarene exhibited association constants of 106 – 108 M-1, and required a central solvent

molecule as a space filling guest (either o-dichlorobenzene or chloroform). The strong

hydrogen bonding of ditopic calixarenes led to the observation of an overlap concentration

(C*) in the solution viscosity versus concentration profile as well as the ability to draw fibers

from solution. Furthermore, the introduction of a tetrafunctional calixarene resulted in

non-covalent networks in which greater than 99% of the material was associated at only 5

wt% concentration. The gels behaved as solids on short time scales but flowed over longer

time scales.

173 Castellano, R. K.; Clark, R.; Craig, S. L.; Nuckolls, C.; Rebek, J. Emergent mechanical properties of self-assembled polymeric capsules. Proc Natl Acad Sci USA 2000, 97, 12418-21.

54

Figure 2.8. Association of ditopic self-complementary tetraurea functional calixarenes.

Reprinted from Castellano et al.174 Copyright 2000, with permission from the National

Academy of Sciences, U.S.A.

174 Castellano, R. K.; Clark, R.; Craig, S. L.; Nuckolls, C.; Rebek, J. Emergent mechanical properties of self-assembled polymeric capsules. Proc Natl Acad Sci USA 2000, 97, 12418-21.

55

2.5 Combining Hydrogen Bonding with other Non-Covalent Interactions

The combining of multiple non-covalent interactions is currently a topic of intense

study. DNA, the paradigm of supramolecular assembly is built up from interactions

including hydrogen bonding, electrostatic interactions175 due to the charged phosphodiester

linkages, hydrophobic interactions and π-π stacking of the nucleobases.176 This combination

of non-covalent interactions enables DNA to perform functions such as replication and

protein synthesis necessary for life.177 As in DNA, combining multiple non-covalent

assembly mechanisms results in versatility and tunable properties, particularly when the

interaction mechanisms respond to different stimuli. Recently, Weck et al. have introduced

both metal-ligand and hydrogen bonding interactions into ROMP block copolymers (Figure

2.9).178 The polymers consisted of blocks of palladium sulfur-carbon-sulfur (SCS) pincer

complexes (which bind nitrile groups), and diacyldiaminopyridine (which binds to thymine)

functionalized ROMP monomers. The presence of the metal coordinating groups was found

not to affect the hydrogen bonding capabilities of the diacyldiaminopyridine containing block

copolymers, suggesting orthogonality of the association mechanisms.

175 Herbert, H. E.; Halls, M. D.; Hratchian, H. P.; Raghavachari, K. Hydrogen-Bonding Interactions in Peptide Nucleic Acid and Deoxyribonucleic Acid: A Comparative Study. Journal of Physical Chemistry B 2006, 110, 3336-43. 176 Vanommeslaeghe, K.; Mignon, P.; Loverix, S.; Tourwe, D.; Geerlings, P. Influence of Stacking on the Hydrogen Bond Donating Potential of Nucleic Bases. Journal of Chemical Theory and Computation 2006, 2, 1444-52. 177 Voet, D.; Voet, J. G., Biochemistry. John Wiley and Sons: New York, 1995; p 1361. 178 Nair, K. P.; Pollino, J. M.; Weck, M. Noncovalently Functionalized Block Copolymers Possessing Both Hydrogen Bonding and Metal Coordination Centers. Macromolecules 2006, 39, 931-40.

56

Figure 2.9. Dual side chain non-covalent interaction modes including both hydrogen bonding

and metal-ligand interactions. Reprinted with permission from Nair et al.179 Copyright 2006,

American Chemical Society.

179 Nair, K. P.; Pollino, J. M.; Weck, M. Noncovalently Functionalized Block Copolymers Possessing Both Hydrogen Bonding and Metal Coordination Centers. Macromolecules 2006, 39, 931-40.

57

Recently, Schubert reported on the use of both metal-ligand and UPy hydrogen bonding

interactions in the main chain using a heterotelechelic poly(ε-caprolactone). 180 Highly

associated non-covalent polymers were formed on the addition of iron salts to a

poly(ε-caprolactone) containing UPy and terpyridine end groups. Sudden decreases in melt

viscosity at temperatures ranging from 100 to 127 oC were attributed to dynamics of the

metal-ligand associations. Replacing iron with zinc salt decreased the temperature of this

transition to 70-80 oC.

2.6 Reversible Attachment of Guest Molecules via Hydrogen Bonding

Reversible attachment of small molecules through recognition processes in hydrogen

bonding polymers is an area of current interest. Even in homopolymer blended with small

molecule hydrogen bonding groups, novel morphologies and behaviors are observed. In work

from ten Brinke et al.,181 poly(4-vinylpyridine) was blended with the small molecule

pentadecylphenol. At a ratio of pyridine to phenol of 1:1, a microphase separated texture

composed of lamella was observed from SAXS in which a second diffraction maxima occurs

at two times the primary scattering maximum (2q*). Heating this blend resulted in a marked

decrease and broadening of the SAXS maxima at 65 oC, which was attributed to a transition

from a microphase separated morphology to a homogeneous system. This ODT was

180 Hofmeier, H.; Hoogenboom, R.; Wouters, M. E. L.; Schubert, U. S. High Molecular Weight Supramolecular Polymers Containing Both Terpyridine Metal Complexes and Ureidopyrimidinone Quadruple Hydrogen-Bonding Units in the Main Chain. J Am Chem Soc 2005, 127, 2913-21. 181 Ruokolainen, J.; Torkkeli, M.; Serimaa, R.; Komanschek, E.; ten Brinke, G.; Ikkala, O. Order-Disorder Transition in Comblike Block Copolymers Obtained by Hydrogen Bonding between Homopolymers and End-Functionalized Oligomers: Poly(4-vinylpyridine)-Pentadecylphenol. Macromolecules 1997, 30, 2002-7.

58

confirmed with rheological measurements in which the storage modulus G’ exhibited a

sudden decrease at 65 oC, and G’ and G” began to follow scaling relationships expected for

homopolymer melts (G’ ~ ω2, G”~ ω).

In the case of hydrogen bonding block copolymers, reversible attachment of guests

holds promise to place guest molecules in specific domains and to influence the size and

morphology of those domains. The morphology of block copolymers is classically controlled

using changes in the volume fractions of various blocks, which are related to the relative

molecular weights of each block. In AB diblock copolymers, this ranges from spherical

dispersed phases at low volume fractions to cylinders and gyroid structures with increasing

volume fraction and finally lamella at near equal volume fractions for the two monomers.

The introduction of small molecule hydrogen bonding groups serves to control this volume

fraction through selective incorporation into particular domains, thereby influencing the

morphology. For example, ten Brinke et al. studied blends of pentadecylphenol and

poly(styrene-b-4-vinylpyridine).182,183 In this case, two length scales were observed: a longer

length scale (20-90 nm) corresponding to microphase separation between polystyrene and

poly(4-vinylpyridine) blocks and a smaller length scale (3.5 nm) corresponding to lamellar

structure in the poly(4-vinylpyridine)-pentadecylphenol comb domains.

182 Polushkin, E.; Alberda van Ekenstein, G. O. R.; Knaapila, M.; Ruokolainen, J.; Torkkeli, M.; Serimaa, R.; Bras, W.; Dolbnya, I.; Ikkala, O.; ten Brinke, G. Intermediate Segregation Type Chain Length Dependence of the Long Period of Lamellar Microdomain Structures of Supramolecular Comb-Coil Diblocks. Macromolecules 2001, 34, 4917-22. 183 Albderda van Ekenstein, G.; Polushkin, E.; Nijland, H.; Ikkala, O.; ten Brinke, G. Shear Alignment at Two Length Scales: Comb-Shaped Supramolecules Self-Organized as Cylinders-within-Lamellar Hierarchy. Macromolecules 2003, 36, 3684-8.

59

In block lamellar diblock copolymers, the molecular weight dependence of the long

period typically follows a dependence on molecular weight to the 0.67 power in the case of

strong phase separation (D ~ N0.67). However, in the case of poly(styrene-b-4-vinylpyridine)

with pentadecylphenol an exponent of 0.8 was observed suggesting weaker phase separation,

which was attributed to the partial miscibility of the pentadecylphenol with the styrenic

lamella. High shear stability of hydrogen bonded pentadecylphenol and

poly(4-vinylpyridine) groups below their ODT was demonstrated at strains of 100% and 0.5

Hz frequency. In the case of poly(styrene-b-4-vinylpyridine) blends with pentadecylphenol,

shearing was a useful means of orienting the lamella parallel to the shear direction and the

hydrogen bonded comb structure was re-developed upon cooling.184 Shearing of blends

with cylindrical morphology resulted in the orientation of the hexagonally packed cylinders

along the shear direction. The soluble pentadecylphenol was extracted from the oriented

cylinders of poly(4-vinylpyridine) using methanol, resulting in a nanoporous structure.185

ten Brinke’s group has also studied the hydrogen bonding attachment of octyl gallate

(an octyl functionalized trihydroxybenzene) to poly(isoprene-b-vinylpyridine) block

copolymers containing small 2- or 4-vinylpyridine blocks of 10 - 28 units. 186 For

4-vinylpyridine block copolymers, the morphologies consisted of cylinders of 4-vinylpyridine

184 Makinen, R.; Ruokolainen, J.; Ikkala, O.; De Moel, K.; ten Brinke, G.; De Odorico, W.; Stamm, M. Orientation of Supramolecular Self-Organized Polymeric Nanostructures by Oscillatory Shear Flow. Macromolecules 2000, 33, 3441-6. 185 Makki-Ontto, R.; de Moel, K.; de Odorico, W.; Ruokolainen, J.; Stamm, M.; ten Brinke, G.; Ikkala, O. "Hairy Tubes": Mesoporous Materials Containing Hollow Self-Organized Cylinders with Polymer Brushes at the Walls. Adv Mater 2001, 13, 117-21. 186 Bondzic, S.; DeWit, J.; Polushkin, E.; Schouten, A. J.; ten Brinke, G.; Ruokolainen, J.; Ikkala, O.; Dolbnya, I.; Bras, W. Self-Assembly of Supramolecules Consisting of Octyl Gallate Hydrogen Bonded to Polyisoprene-block-poly(vinylpyridine) Diblock Copolymers. Macromolecules 2004, 37, 9517-24.

60

and octyl gallate in a polyisoprene matrix and cylinder diameters increased with octyl gallate

content. This was unsurprising given that the hard phase weight fraction ranged from 15.8

wt% to 25.2 wt%. For the poly(2-vinylpyridine) blocks, the attachment led to different

morphologies depending on the amount of octyl gallate present. The morphology shifted to

lamellar morphology with increasing octyl gallate content, and the morphologies exhibited

temperature dependence such that the lamellar morphology showed a decrease in lamellar

spacing with temperature and a transition to cylindrical morphology at 150 oC (Figure 2.10).

Shifting of the morphology and the changing sizes of the morphological features was

attributed to dissociation of hydrogen bonding guests and the poly(2-vinylpyridine) blocks

were thought to relax from a stretched state upon the dissociation of the octyl gallate.

Hydrogen bonding was observed to decrease with heating above 100 oC using FTIR so that at

190 oC, almost all of the pyridine groups were not hydrogen bonded.

61

Figure 2.10. Phase diagram of poly(isoprene-b-2-vinylpyridine) with octyl gallate, indicating

the transition between different morphologies with octyl gallate content and temperature. (D

= disordered, S = spherical, H = hexagonal, L = lamellar, L2 = lamellar with reduced spacing

and I = intermediate state). Reprinted with permission from Bondzic et al.187 Copyright 2004,

American Chemical Society.

187 Bondzic, S.; DeWit, J.; Polushkin, E.; Schouten, A. J.; ten Brinke, G.; Ruokolainen, J.; Ikkala, O.; Dolbnya, I.; Bras, W. Self-Assembly of Supramolecules Consisting of Octyl Gallate Hydrogen Bonded to Polyisoprene-block-poly(vinylpyridine) Diblock Copolymers. Macromolecules 2004, 37, 9517-24.

62

Thomas et al. studied the reversible attachment of liquid crystalline side chains to

poly(acrylic acid-b-styrene) block copolymers via hydrogen bonding of imidazole groups to

mesogens.188 The reversibility of the attachment of the mesogens, which tended to form

smectic phases, was proposed to play an integral role in the ability of these block copolymers

to undergo reorientation of the lamella relative to external electrodes with an alternating

electric field above Tg. Comparisons with covalently bound chromophores showed that

reorientation of the lamella did not occur. Further studies involving poly(methacrylic

acid-b-styrene) with imidazole containing mesogens allowed the fabrication of temperature

dependent photonic bandgap materials which exhibited reflectivity maxima that reversibly

changed as a function of temperature from 560 to 569 nm from 40 to 70 oC.189

Recently, ten Brinke and Ikkala’s group demonstrated the attachment of ionic

molecules (zinc dodecylbenzene sulfonate) to poly(styrene-b-4-vinylpyridine) via

coordination of the zinc ions to the pyridine rings.190 These blends possessed lamellar

morphology, even at low weight fractions (0.23) of the 4-vinylpyridine and zinc

dodecylbenzene sulfonate, possibly due to the strength of the ionic interactions. Strong

segregation due to ionic interactions often leads to altered morphology in ionomers.191

188 Chao, C. Y.; Li, X.; Ober, C. K.; Osuji, C.; Thomas, E. L. Orientational Switching of Mesogens and Microdomains in Hydrogen Bonded Side-Chain Liquid-Crystalline Block Copolymers Using AC Electric Fields. Adv Funct Mater 2004, 14, 364-70. 189 Osuji, C.; Chao, C. Y.; Bita, I.; Ober, C. K.; Thomas, E. L. Temperature-Dependent Photonic Bandgap in a Self-Assembled Hydrogen Bonded Liquid-Crystalline Block Copolymer. Adv Funct Mater 2002, 12, 753-58. 190 Valkama, S.; Ruotsalainen, T.; Kosonen, H.; Ruokolainen, J.; Torkkeli, M.; Serimaa, R.; ten Brinke, G.; Ikkala, O. Amphiphiles Coordinated to Block Copolymers as a Template for Mesoporous Materials. Macromolecules 2003, 36, 3986-91. 191 Mani, S.; Weiss, R. A.; Williams, C. E.; Hahn, S. F. Microstructure of Ionomers Based on Sulfonated Block Copolymers of Polystyrene and Poly(ethylene-alt-propylene). Macromolecules 1999, 32, 3663-70.

63

Although the crystallinity of the zinc dodecylbenzene sulfonate was suppressed in the blends,

a lamellar packing present in the pure salt was observed in the blends, indicating a lamella

within lamella structure. The zinc salt was selectively removed using methanol washes.

2.7 Conclusions and Summary

Hydrogen bonding interactions have gained significant attention recently, as a means of

introducing novel, thermoreversible interactions to polymers, influencing both physical

property performance as well as morphology and processing behavior. The recent

development of multiple hydrogen bonding groups which associate more strongly than single

hydrogen bonds has led to greater control of physical and mechanical properties.

The introduction of hydrogen bonding groups in block copolymers leads to increased

hydrogen bonding interactions through locally increased hydrogen bonding group

concentration and cooperativity of the hydrogen bonding groups. Increased χ parameters in

hydrogen bonding block copolymers result in improved phase separation and the need for

fewer repeating units to achieve phase separation. This phase separation often exhibits a

greater temperature dependence and order-disorder transitions are linked directly to the

hydrogen bonding phenomenon. In the case of complementary hydrogen bonding groups,

such as nucleobases, introduction of guest molecules and complexation of complementary

polymer blocks is achievable. Interesting morphologies are observed in both the solution and

solid state for hydrogen bonding block copolymers.

Telechelic hydrogen bonding functionality has been the focus of great attention in

recent years. Telechelic functionality results in a simpler system for studying hydrogen

64

bonding, although microphase separation can still complicate the system in the solid state.

Self-complementary quadruple hydrogen bonding ureidopyrimidone (UPy) groups have been

a strong focus in this area. Solution rheology is a particularly powerful tool for studying

these systems and both concentration and the present of “chain blocker” monofunctional

hydrogen bonding groups control the effective molecular weight in solution.

65

Chapter 3. Review of the Literature – Michael Addition Reactions in

Macromolecular Design for Emerging Technologies

(Mather, B.D.; Viswanathan, K.; Miller, K.M.; Long, T.E. Progress in Polymer Science 2006,

31, 487-531) Reproduced with permission. Copyright 2006 Elsevier.

3.1 Abstract

The Michael addition reaction is a versatile synthetic methodology for the efficient

coupling of electron poor olefins with a vast array of nucleophiles. This review outlines the

role of the Michael addition reaction in polymer synthesis with attention to applications in

emerging technologies including biomedical, pharmaceutical, optoelectronic, composites,

adhesives, and coatings. Polymer architectures, which broadly range from linear

thermoplastics to hyperbranched polymers and networks are achievable. The versatility of the

Michael reaction in terms of monomer selection, solvent environment, and reaction

temperature permits the synthesis of sophisticated macromolecular structures under

conditions where other reaction processes will not operate. The utility of the Michael addition

in many biological applications such as gene delivery, polymer drug conjugates, and tissue

scaffolds is related to macromolecular structure.

3.2 Motivation and Scientific Rationale

The Michael addition reaction, which is also commonly termed conjugate addition, has

recently gained increased attention as a polymer synthesis strategy for tailored

66

macromolecular architectures. The Michael addition, named for Arthur Michael, is a facile

reaction between nucleophiles and activated olefins and alkynes in which the nucleophile

adds across a carbon-carbon multiple bond.192 The Michael addition benefits from mild

reaction conditions, high functional group tolerance, a large host of polymerizable monomers

and functional precursors as well as high conversions and favorable reaction rates.193 The

Michael reaction lends itself to both step growth194 and chain growth polymerization195 and

has been employed in the synthesis of linear, graft, hyperbranched, dendritic and network

polymers. Furthermore, post-polymerization modification196 and coupling of biological and

synthetic polymers are often facilitated by the Michael reaction.197 These features make the

Michael addition reaction well-suited to numerous emerging technologies including

biomedical applications such as gene transfection, 198 cell scaffolds 199 and tissue

replacements.193

The Michael addition reaction enables a wide range of polymers from diverse

monomers, and corresponding polymers are prepared in environments in which other

192 Michael, A. On the addition of sodium acetacetic ether and analogous sodium compounds to unsaturated organic ethers. Am Chem J 1887, 9, 115. 193 Vernon, B.; Tirelli, N.; Bachi, T.; Haldimann, D.; Hubbell, J. Water-borne, in situ crosslinked biomaterials from phase-segregated precursors. J Biomed Mater Res 2003, 64A, 447-56. 194 Vaccaro, E.; Scola, D. A. New applications of polyaminoquinones. CHEMTECH 1999, 29, 15-23. 195 van Beylen, M.; Bywater, S.; Smets, G.; Swarc, M.; Worsfold, D. J. Developments in anionic polymerization - a critical review. Adv Polym Sci 1988, 86, 87-143. 196 Tokura, S.; Nishi, N.; Nishimura, S.; Ikeuchi, Y. Studies on chitin X. Cyanoethylation of chitin. Polym J 1983, 15, 553-6. 197 Morpurgo, M.; Veronese, F. M.; Kachensky, D.; Harris, J. M. Preparation and characterization of poly(ethylene glycol) vinyl sulfone. Bioconjug Chem 1996, 7, 363-8. 198 Richardson, S. C. W.; Pattrick, N. G.; Stella Man, Y. K.; Ferruti, P.; Duncan, R. Poly(amidoamine)s as potential nonviral vectors: ability to form interpolyelectrolyte complexes and to mediate transfection in vitro. Biomacromolecules 2001, 2, 1023-8. 199 Ferruti, P.; Bianchi, S.; Ranucci, E.; Chiellini, F.; Caruso, V. Novel poly(amido-amine)-based hydrogels as scaffolds for tissue engineering. Macromol Biosci 2005, 5, 613-22.

67

polymerization mechanisms will not operate. In biological applications such as protein

derivitization the mild Michael addition reaction conditions are favorable since high

temperatures, oxidizing radicals, and organic solvents are not feasible.200 Furthermore, the

Michael addition has recently found utility for the synthesis of crosslinked polymers such as

hydrogels,201 thermoset resins,202 and coatings, where rapid cure and high conversions are

necessary for performance. Few polymerizations offer sufficient rates to permit room

temperature cure, and industrial coatings are often limited to toxic and environmentally

hazardous isocyanate containing monomers. The Michael addition proceeds rapidly at room

temperature, offers low cure times, and involves less toxic precursors. Non-linear optical

materials were also realized using the Michael addition, which benefits from the absence

volatile byproducts. 203 The Michael addition is also ubiquitous in classical polymer

chemistry, such as the anionic polymerization of alkyl methacrylates and cyanoacrylates.

The Michael addition involves the addition of a nucleophile, also called a “Michael

donor,” to an activated electrophilic olefin, the “Michael acceptor”, resulting in a “Michael

adduct”, as shown in Figure 3.1b. Although the Michael addition is generally considered

the addition of enolate nucleophiles to activated olefins, a wide range of functional groups

possess sufficient nucleophilicity to perform as Michael donors. Reactions involving

200 Elbert, D. L.; Pratt, A. B.; Lutolf, M. P.; Halstenberg, S.; Hubbell, J. A. Protein delivery from materials formed by self-selective conjugate addition reactions. J Contr Rel 2001, 76, 11-25. 201 Rizzi, S. C.; Hubbell, J. A. Recombinant protein-co-PEG networks as cell-adhesive and proteolytically degradable hydrogel matrixes. Part I: Development and physicochemical characteristics. Biomacromolecules 2005, 6, 1226-38. 202 Pavlinec, J.; Moszner, N. Photocured polymer networks based on multifunctional β-ketoesters and acrylates. J Polym Sci Part A: Polym Chem 1997, 10, 165-78. 203 Abbotto, A.; Beverina, L.; Chirico, G.; Facchetti, A.; Ferruti, P. G., M; Pagani, G. A. Crosslinked poly(amido-amine)s as superior matrices for chemical incorporation of highly efficient organic nonlinear optical dyes. Macromol Rapid Commun 2003, 24, 397-402.

68

non-enolate nucleophiles such as amines, thiols, and phosphines are typically referred to as

“Michael-type additions”. In this review we will refer to Michael-type addition reactions with

all nucleophilic donors as Michael additions. The Michael acceptor possesses an electron

withdrawing and resonance stabilizing activating group, which stabilizes the anionic

intermediate. Michael addition acceptors are far more numerous and varied than donors,

due to the plethora of electron withdrawing activating groups that enable the Michael

addition to olefins and alkynes. Acrylate esters, acrylonitrile, acrylamides, maleimides, alkyl

methacrylates, cyanoacrylates and vinyl sulfones serve as Michael acceptors and are

commercially available. Less common, but equally important, vinyl ketones, nitro ethylenes,

α,β-unsaturated aldehydes, vinyl phosphonates, acrylonitrile, vinyl pyridines, azo compounds

and even β-keto acetylenes and acetylene esters also serve as Michael acceptors.204

204 Gimbert, C.; Lumbierres, M.; Marchi, C.; Moreno-Manas, M.; Sebastian, R. M.; Vallribera, A. Michael additions catalyzed by phosphines. An overlooked synthetic method. Tetrahedron 2005, 61, 8598-605.

69

Figure 3.1 a) Arthur Michael (1855-1942), who discovered the Michael addition reaction. b)

Schematic depiction of the Michael addition reaction. Nu = nucleophile, EWG = electron

withdrawing group, BH = protic source to neutralize Michael adduct.

a) b)

70

3.3. Introduction to the Michael Addition Reaction

The Michael reaction typically refers to the base-catalyzed addition of a nucleophile

such as an enolate anion (Michael donor) to an activated α,β-unsaturated carbonyl-containing

compound (Michael acceptor) as in Figure 3.1b.205206207208

- 209 However, over the years, the scope

of this reaction has increased dramatically to include a broad range of acceptors and the

Michael-type additions of non-carbon donors. Due to the many types of Michael additions

in the literature, we will focus here on investigating the mechanism and kinetics of only a few

examples, namely the carbon-carbon bond forming Michael addition (referred to as the

carbon-Michael addition), nitrogen (amine or aza) Michael additions, and the reaction of

thiols with Michael acceptors.

3.3.1 Mechanism of the Carbon-Michael Addition Reaction

One of the most well-known carbon-Michael transformations is the base-catalyzed

addition of ethyl acetoacetate to methyl acrylate.210 The mechanism of the reaction is fairly

straightforward, with every step being in equilibrium and thermodynamically dependent on

the relative strengths of the base and the type of acetoacetate. The acetoacetate is first

205 Bergman, E. D.; Ginsburg, D.; Pappo, R. The Michael reaction. Org React 1959, 10, 179-556. 206 Little, R. D.; Masjedizadeh, M. R.; Wallquist, O.; McLoughlin, J. I. The Intramolecular Michael reaction. Org React 1995, 47, 315-552. 207 Jung, M. E., Stabilized nucleophiles with electron deficient alkenes and alkynes. In Comprehensive Organic Synthesis, Trost, B. M., Ed. Pergamon: Oxford, 1991. 208 Michael, A. J. Ueber die addition von natriumäcetessig- und natriummälonsäureathern zu den aethern ungesattigter sauren. Prakt Chem 1887, 35, 349-56. 209 Connor, R.; McClellan, W. R. The Michael condensation. V. The influence of the experimental conditions and the structure of the acceptor upon the condensation. J Org Chem 1938, 3, 570-7. 210 Albertson, N. F. Alkylation with non-ketonic Mannich bases. Aminothiazoles and pyrrole. J Am Chem Soc 1948, 70, 669-70.

71

deprotonated by the base, providing an enolate anion (Michael donor) in equilibrium (Figure

3.2). The enolate anion then reacts in a 1,4-conjugate addition to the olefin of the acrylate

(Michael acceptor). The carbonyl of the acrylate stabilizes the resulting anion until proton

transfer occurs, regenerating the base. The overall driving force for the conjugate addition

is the enthalpic change that accompanies replacement of a π-bond with a σ-bond. Thus,

there is the preference for 1,4-addition over 1,2-addition. In some cases however,

kinetically controlled reaction conditions can afford attack at the carbonyl carbon rather than

at the β-carbon of the olefin.211,212

From Figure 3.2, one can observe that the rate determining step is the attack of the

enolate anion on the activated olefin. The reaction rate is therefore second order overall and

first order with respect to the enolate anion and the olefin acceptor. The concentration of the

enolate is a function of the base strength and the Keq of the deprotonation of the active

methylene proton. It follows that the equilibrium constant is dependent on the relative

strength of the base and the structure of the acetoacetate.

211 Little, R. D.; Masjedizadeh, M. R.; Wallquist, O.; McLoughlin, J. I. The intramolecular Michael reaction. Org React 1995, 47, 315-52. 212 Schultz, A. G.; Lee, Y. K. Conjugate and direct addition of ester enolates to cyclohexenone. Selective control of reaction composition. J Org Chem 1976, 41, 4044-5.

72

O

O OEt

M+ -OEt

H H

acetoacetate donor

basecatalyst

O

O OEt

RO

O OEt

H

O

OCH3

acrylate acceptor

O

O OEt

O

OCH3

H+H

O

O OEt

O

OCH3

H

adduct

Keq

slow

Figure 3.2. General carbon-Michael reaction mechanistic scheme.

73

It is important to note that the product of the first Michael addition has a remaining

active methylene proton which can undergo a second addition to another acrylate (Figure 3.3).

Clemens et al. have documented that the second pKa is expected to have a value of 13 (versus

the pKa of the initial active proton of 12).213 The second deprotonation therefore has a

different equilibrium constant (Keq) and it is assumed that the concentration of the first

Michael adduct will be low. As a result, the concentration of the enolate at any rate

(especially in the early stages of the reaction) is not strongly affected by this second reaction.

It follows that a rate law can be determined for the above reaction sequence. Writing the

reactions in terms of the Michael addition, we arrive at the kinetic equations:

O

O OR

O

O OR

H

Keq+ B + BH

O

O OR

H

+O

OR'

k2

slowPolyesters

And subsequent rate equations:

Keq = [AcAc-][BH+] / [AcAc][B]

Rate = k2[AcAc-][Acrylate] = k2Keq([B] / [BH+])[AcAc][Acrylate]

213 Clemens, R. J.; Rector, F. D. A comparison of catalysts for crosslinking acetoacetylated resins via the Michael reaction. J Coat Tech 1989, 61, 83-91.

[3.1] [3.2]

[3.3]

[3.4]

74

O

O OEt

O

OCH3

HO

O OEt-OEt

O

OCH3 O

O OEt

O

OCH3H3CO

OO

OCH3

Figure 3.3. Second Michael addition of acetoacetate group to methyl acrylate.

75

3.3.1.1 Effect of Base Strength

The choice of base catalyst has a tremendous effect on the reaction kinetics. As

previously noted, the concentration of the enolate and therefore the value of Keq is highly

dependent on the relative base strength. For strong bases, Keq will lie far to the right and the

concentration of the enolate anion is then approximately equal to the concentration of the

base (achieving a steady state concentration). In the resulting rate expression (Eq. 3.5), there

is a pseudo first-order dependence on acrylate concentration, where kobs is a function of base

concentration.

Rate = kobs[Acrylate] [3.5]

In the case of weaker base catalysts, Keq has a moderate value, but is not large. This

introduces the equilibrium constant into the rate law and results in second order behavior (Eq.

3.4). Clemens et al. completed an extensive study on the effect of base strength on

reaction kinetics and molecular weight when the Michael addition is used to prepare

crosslinked acetoacetate resins for thermoset coatings.214 In a model study, Clemens

analyzed the activity of weaker bases such as TMG (tetramethylguanidine), triethylamine,

DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), and DBN (1,5-diazabicyclo[4.3.0]non-5-ene) and

found that the rate of the reaction was dependent on catalyst concentration as indicated in Eq.

3.4. For strong bases such as hydroxide, a steady-state concentration of enolate anion is

achieved and pseudo-first order kinetics were observed (Eq. 3.5).


76

The pKa of the Michael donor is important to the choice of base catalyst, which must

have a pKa for its conjugate acid in the same range as the Michael donor. Stronger bases

such as tetramethylguanidine, with a pKa of 13.6 in its protonated form, are needed in the

case of the carbon Michael addition of enolates due to the high pKa of the acetoacetate groups

(pKa1 ~ 12, pKa2 ~ 13.6). Base catalysts are often unnecessary in the case of amines,

because of the strong nucleophilicity of the nitrogen atom, whereas weak bases aid in

deprotonation of thiols.

3.3.1.2 Effect of Solvent

Typical solvents for the carbon-Michael reaction include methanol, ethanol, diethyl

ether, tetrahydrofuran, benzene, xylene, dioxane and mixtures of these solvents. Initially,

protic solvents were desirable in the carbon-Michael reaction to promote rapid proton transfer

and to stabilize charged intermediates, however, Schlessinger’s group has shown that high

yielding reactions were also achieved using aprotic solvents.215216

- 217 The choice of solvent

strongly depends on the solubility of the catalyst, donor, and acceptor as well as sensitivity to

side reactions. For example, if the reactants or products are susceptible to alcoholysis (ester

exchange or hydrolysis), self-condensation of the substrate or the ‘retro-Michael’ reaction, a

non-hydroxylic solvent is desirable.218,219 In some cases, reactions are carried out in the

215 Cregge, R. J.; Herrmann, J. L.; Richman, J. E.; Romanent, R. F.; Schlessinger, R. H. The conjugate addition of a glyoxalate derived carbonyl anion equivalent and its application to the synthesis of 1,4-dicarbonyl compounds. Tet Lett 1973, 14, 2595-98. 216 Herrmann, J. L.; Richman, J. E.; Schlessinger, R. H. A highly reactive carbonyl anion equivalent derived from ethyl glyoxalate and its conjugate addition to Michael receptors. Tet Lett 1973, 14, 2599-602. 217 Cregge, R. J.; Herrmann, J. L.; Schlessinger, R. H. A versatile and reactive Michael receptor for the synthesis of 1,4 -dicarbonyl compounds. Tet Lett 1973, 14, 2603-6. 218 Bergman, E. D.; Ginsburg, D.; Pappo, R. The Michael reaction. Org React 1959, 10, 179-556.

77

absence of solvent, especially for network or coating applications.

3.3.1.3 Effect of Substrate

As mentioned before, the initial step of the carbon-Michael addition is deprotonation of

an active methylene proton. Thus, donors must stabilize the resulting negative charge.

Examples of functional groups which stabilize enolate donors include ketones, aldehydes,

nitriles, amides, nitrones, sulfones, malonates and acetoacetates. A great deal of thought

must be directed to the selection of the proper donor and base, and knowledge of the pKa of

these various species is critical. Furthermore, strongly bases such as hydroxide and

methoxide may promote side reactions such as ester hydrolysis, so non-nucleophilic bases are

often desirable.

Acceptors in the carbon-Michael addition are typically olefins that are activated for

nucleophilic attack. The resulting anion from nucleophilic attack of the donor must also be

stabilized for the reaction to occur. Thus, the use of α,β-unsaturated carbonyl compounds

is prevalent in Michael addition chemistry. The reactivity of the acceptor will decrease if

the substituent is electron rich, such as in the case of alkyl, aryl or carboethoxy substituted

olefins such as styrene derivatives or vinyl ethers. Sterics are also an important factor.

The larger the groups substituted at the α and β positions, the slower the reaction rate,

although this can be offset by stronger polar effects.220,221 Differences in reactivity between

219 Bickel, C. L. The addition of malonic esters to an acetylenic ketone. J Am Chem Soc 1950, 72, 1022-3. 220 Connor, R.; McClellan, W. R. The Michael condensation. V. The influence of the experimental conditions and the structure of the acceptor upon the condensation. J Org Chem 1938, 3, 570-7. 221 Ingold, C. K.; Perren, E. A.; Thorpe, J. F. Ring-chain tautomerism. III. The occurrence of tautomerism of the three-carbon (glutaconic) type between a homocyclic compound and its unsaturated open-chain isomeride. J Chem Soc 1922, 121, 1765-89.

78

acceptors require differences in nucleophilicity of the Michael donors. For instance, alkyl

methacrylates are relatively poor Michael acceptors. Thus, stronger nucleophiles such as

carbanions are necessary for successful Michael addition to alkyl methacrylates. Better

acceptors such as alkyl acrylate or acrylamide groups readily accept amine and thiol

nucleophiles.

Alkynes have also been utilized as Michael acceptors. In Figure 3.4, electron-rich

enamines react readily with activated alkynes in refluxing ethanol.222 Products of Michael

reactions with alkynes have the additional variables of stereochemistry of the unsaturated

product, and regiochemistry of addition for disubstituted alkynes acceptors.

222 Wang, M. X.; Miao, W. S.; Cheng, Y.; Huang, Z. T. A systematic study of reaction of heterocyclic enamines with electrophilic alkynes: a simple and efficient route to 2-pyridinone-fused heterocycles. Tetrahedron 1999, 55, 14611-22.

79

NH

H

O

OCH3 H C CO

OEt

+EtOH

reflux

NH O

OCH3

HCO2Et

H

Figure 3.4. Michael Addition involving an alkyne acceptor.

80

3.3.1.4 Other Carbon-Michael Catalysts

Although base-catalysis is most prominently used in the carbon-Michael addition, the

reaction is also catalyzed with acids, particularly in the case of Lewis acids. Some of the

earlier examples include the use of boron trifluoride, aluminum trichloride, and zinc

chloride.223 In these cases, the Lewis acid coordinates to the carbonyl of the acrylate to

activate the olefin (Figure 3.5). The coordinated complex will then react with the

nucleophile to obtain the same adduct as in the base-catalyzed Michael addition. In the case

where silyl enolates are donors, the reaction is often referred to as the Mukaiyama-Michael

reaction.

Researchers have used Lewis acid complexes to their advantage over the years,

especially in the area of enantioselective additions. For example, Heathcock’s group has

shown that silyl enolates will react enantioselectively with α,β-unsaturated ketones in the

presence of TiCl4 (Figure 3.6).224 In the area of enantioselective carbon-Michael additions,

the reader is directed to two recent reviews published on the subject.225,226

Phosphines also catalyze the carbon-Michael reaction.227 The reaction sequence

begins with nucleophilic attack of the phosphine on the β-position of the olefin, generating a

reactive phosphonium ylid (Figure 3.7). The resulting anion can then either react as a

223 Hauser, C. R.; Breslow, D. S. Condensations. XII. A general theory for certain carbon--carbon condensations effected by acidic and basic reagents. J Am Chem Soc 1940, 62, 2389-92. 224 Heathcock, C. H.; Uehling, D. E. Acyclic stereoselection. Part 34. Stereoselection in the Michael addition reaction. 4. Diastereofacial preferences in Lewis acid-mediated additions of enolsilanes to chiral enones. J Org Chem 1986, 51, 279-80. 225 Sibi, M.; Manyem, S. Enantioselective conjugate additions. Tetrahedron 2000, 56, 8033-61. 226 Krause, N.; Hoffman-Röder, A. Recent advances in catalytic enantioselective Michael additions. Synthesis 2001, 2, 171-96. 227 Gimbert, C.; Lumbierres, M.; Marchi, C.; Moreno-Manas, M.; Sebastian, R. M.; Vallribera, A. Michael additions catalyzed by phosphines. An overlooked synthetic method. Tetrahedron 2005, 61, 8598-605.

81

nucleophile or as a base. If an acetoacetate is present in the reaction, the ylid deprotonates

the acetoacetate first, which adds to the β-position of another olefin in a Michael fashion.

Proton transfer then results in regeneration of the initial olefin and the phosphine catalyst.

82

O

O OHR

LAO

R'O

O

O OR

O

OR'H

H

O

R'O

LA

Figure 3.5. Lewis-acid catalyzed Michael addition reaction.

83

PhO

CH3

CH3

+

OSi(CH3)3 TiCl4

CH2Cl2

PhO

CH3

CH3

O

single product observed

Figure 3.6. Stereoselective Michael addition between enone and silyl enolate in the presence

of TiCl4.

84

R3P R' R'R3P

R'R3P

O

H3CO

O

+

+ R'R3P

O

H3CO

O

H

+

O

H3CO

O

HR'+ H3CO

O O

R'

H

R'R3P

R3P R'+H3CO

O O

R'

HH3CO

O O

R'

H+

phosphonium ylid

Figure 3.7. Phosphine catalyzed Michael addition reaction.

85

3.3.2 Heteroatomic Donors in the Michael Addition Reaction

Carbon-based nucleophiles represent only one class of donors used in Michael addition

reactions. Heteroatomic nucleophiles involving nitrogen, sulfur, oxygen and phosphorus

have also been used. In this section, two of these additions will be discussed: the

aza-Michael reaction (amines) and the thiol Michael addition reaction. These are of primary

importance due to the presence of sulfur and nitrogen nucleophiles in biological systems.

3.3.2.1. The aza-Michael Reaction

The nitrogen-donor version of the Michael addition is often referred to as the

aza-Michael reaction. Since only a few concepts will be touched upon here, the reader is

encouraged to investigate several reviews for additional information.228229230

- 231 Since amines

can act as both nucleophiles and bases, no additional base is typically needed in these

reactions. The reaction tends to follow second-order kinetics based on the concentration of

the olefin acceptor and the amine (Figure 3.8).

Primary amines can react with two equivalents of acceptor to form tertiary amines. In

some cases, this second addition affects the observed kinetics, especially as the concentration

of the secondary amine increases. An example is the reaction of methyl amine with ethyl

acrylate, giving an excellent yield of the tertiary amine (Figure 3.9).232

228 Jung, M. E., Stabilized nucleophiles with electron deficient alkenes and alkynes. In Comprehensive Organic Synthesis, Trost, B. M., Ed. Pergamon: Oxford, 1991. 229 Wabnitz, T. C.; Yu, J. Q.; Spencer, J. B. Evidence that protons can be the active catalyst in Lewis acid mediated hetero-Michael addition reactions. Chem Eur J 2004, 10, 484-93. 230 Wabnitz, T. C.; Yu, J. Q.; Spencer, J. B. A general, polymer-supported acid catalyzed hetero-Michael addition. Syn Lett 2003, 7, 1070-2. 231 Wabnitz, T. C.; Spencer, J. B. A general, Brønsted acid-catalyzed hetero-Michael addition of nitrogen, oxygen, and sulfur nucleophiles. Org Lett 2003, 5, 2141-4. 232 McElvain, S. M.; Rorig, K. Piperidine derivatives. XVIII. The condensation of aromatic aldehydes with 1-methyl-4-piperidone. J Am Chem Soc 1948, 70, 1820-5.

86

NH3C CH3

H+

O

OEt

k1EtO2C

NCH3

CH3H

fastEtO2C

NCH3

CH3

Rate = k1[Amine][Acrylate]

Figure 3.8. Aza-Michael addition reaction of dimethylamine with ethyl acrylate.

87

H3C NH2 +O

OEt

60-70 oC

1 hr, 92 %

EtO2C

N

CO2Et

CH3

Figure 3.9. Aza-Michael addition of methyl amine to two equivalents of ethyl acrylate.

88

In the aza-Michael reaction, secondary amines are more nucleophilic than primary

amines and are therefore more reactive. However, it is worth noting that this is highly

dependent on the electronic and steric environment of the amine. For example,

1,4-butanediol diacrylate was allowed to react with 1-(2-aminoethyl)piperazine in an

equimolar ratio (Figure 3.10).233 During the initial part of the experiment, it was found that

there was exclusive reaction with the secondary amine present in the piperazine ring. Only

upon longer reaction times, did reaction occur with the primary amine, which led to

polymerization.

Acid catalyzed aza-Michael additions have also been studied extensively. Spencer and

coworkers have determined a general and efficient way of reacting carbamates (NHCOOR)

with　α,β-unsaturated carbonyl compounds (Figure 3.11), providing precursors to β-amino

acids.234

Vedejs and Gringas have also shown that acids catalyze the aza-Michael addition.235

In Figure 3.12, a tertiary amine, as the donor, adds to the alkyne in the presence of catalytic

p-toluenesulfonic acid. The resulting intermediate further undergoes a Claisen

rearrangement and proton transfer to afford the final α,β-unsaturated amine.

233 Wu, D.; Liu, Y.; He, C.; Chung, T.; Goh, S. Effects of chemistries of trifunctional amines on mechanisms of Michael addition polymerizations with diacrylates. Macromolecules 2004, 37, 6763-70. 234 Wabnitz, T. C.; Yu, J. Q.; Spencer, J. B. Evidence that protons can be the active catalyst in Lewis acid mediated hetero-Michael addition reactions. Chem Eur J 2004, 10, 484-93. 235 Vedejs, E.; Gingras, M. Aza-claisen rearrangements initiated by acid-catalyzed Michael addition. J Am Chem Soc 1994, 116, 579-88.

89

HNN

NH2

O

OO

O

+

O

OO

O

NN

NH2

only product detected after 1.16 hours

O

OO

O

NN

HN

n

50 oC

Figure 3.10. Higher reactivity of secondary amines in aza-Michael addition reactions.

90

O

H2N

O

O

TF2NH (0.1 eq.)

CH3CN, RT 94 %

+O

NH

O

O

Figure 3.11. Acid catalyzed aza-Michael addition.

91

H

PhEt2NC C CO2CH3H3CO2C

pTsOH cat. (10 %)

solvent, 20 oC

+Et2N

Ph

COH

OCH3

H3CO2C

Et2N

Ph

H3CO2C

H

CO2CH3

[3,3] ClaisenEt2N Ph

CO2CH3H3CO2C

- H+Et2N Ph

CO2CH3H3CO2CH

Michael Addition

tautomerization

Figure 3.12. Acid catalyzed aza-Michael addition to activated alkyne acceptors.

92

Lewis acids have also been used to catalyze the aza-Michael reaction, as in Figure 3.13.

The mechanism is thought to occur in an analogous fashion to the carbon-Michael addition

where the Lewis acid coordinates to the carbonyl of the α,β-unsaturated olefin. However,

Spencer has reported that, in the case of weakly basic amine nucleophiles, Brønstead acids

that are formed during the reaction may catalyze the reaction.236

The ability to generate β-amino carbonyl compounds has become increasingly important

to the natural product and pharmaceutical areas. The aza-Michael reaction is a key

transformation which enables the preparation of such compounds. Jørgensen was the first to

report the enantioselective conjugate amine additions (Figure 3.14).237 The TiCl2-BINOL

Lewis acid catalyst coordinates with the N-acyloxazolidinone, creating a chiral environment

in which the primary amine will preferentially attack from one face of the complex, resulting

in the formation of one major diastereomer. The oxazolidinone ring is then removed to

afford the β-amino acid. Although the enantioselectivity is low (maximum enantiomeric

excess of 42 %), the proof of concept was accomplished. The area has grown significantly

and Sibi has published two reviews which discuss stereoselective aza-Michael additions to

generate β-amino acids.238,239

236 Wabnitz, T. C.; Yu, J. Q.; Spencer, J. B. Evidence that protons can be the active catalyst in Lewis acid mediated hetero-Michael addition reactions. Chem Eur J 2004, 10, 484-93. 237 Falborg, L.; Jørgensen, K. A. Asymmetric titanium-catalysed Michael addition of O-benzylhydroxylamine to alpha,beta-unsaturated carbonyl compounds: synthesis of beta-amino acid precursors. J Chem Soc, Perkin Trans 1: Org Bio-org Chem 1996, 23, 2823-6. 238 Sibi, M.; Manyem, S. Enantioselective conjugate additions. Tetrahedron 2000, 56, 8033-61. 239 Liu, M.; Sibi, M. P. Recent advances in the stereoselective synthesis of β-amino acids. Tetrahedron 2002, 58, 7991-8035.

93

Ph

O

H2N

O

O+

10 % catalyst

CH3CN, RTCatalysts:In(OTf)3, Cu(OTf)3, [Pd(CH3CN)4](BF4)2

Ph

O

NH

O

O

Figure 3.13. Lewis acid catalyzed aza-Michael reaction.

94

O N

O

CH3

O PhCH2ONH2, CH2Cl2, -60 oC

O

OTiCl2

O N

O

CH3

O NHOCH2Ph

Figure 3.14. Stereoselective aza-Michael additions.

95

3.3.2.2. Thiols as Michael Donors

Thiols can also be used as heteroatomic donors in the Michael addition. Many of the

same reaction scenarios that were described above can be directly applied to the addition of

thiols to activated olefins. Thiols are generally more nucleophilic than amines, although

bases are often used to deprotonate them due to their comparatively higher acidity. The

thiolate anion is often the active species in Michael additions involving thiols. The thiol

Michael addition reaction rates increase with pH due to the increased concentration of the

thiolate anion.240 The thiol group is a useful Michael donor in biological systems where

thiols are present on proteins in cysteine residues. One primary side reaction in thiol

Michael additions is disulfide bond formation, which often prompts the use of protecting

group chemistry.

Regioselective Michael additions of thiols to asymmetrically substituted fumarate esters

or amides was achieved using lithium salts as Lewis acids or base catalysts to alter the charge

environment around the double bond through coordination of carbonyls or deprotonation of

the thiol (Figure 3.15).241 Enantioselective Michael additions of thiols to methacrylates and

other 1-alkyl acrylates was accomplished with chiral lanthanide catalysts to enantiomeric

excesses as high as 90 % ee.242 Enzyme catalysis of the thiol addition to 2-butenal was

240 Rizzi, S. C.; Hubbell, J. A. Recombinant protein-co-PEG networks as cell-adhesive and proteolytically degradable hydrogel matrixes. Part I: Development and physicochemical characteristics. Biomacromolecules 2005, 6, 1226-38. 241 Kamimura, A.; Murakami, N.; Kawahara, F.; Yokota, K.; Omata, Y.; Matsuura, K.; Oishi, Y.; Morita, R.; Mitsudera, H.; Suzukawa, H.; Kakehi, A.; Shiraic, M.; Okamoto, H. On the regioselectivity for the Michael addition of thiols to unsymmetrical fumaric derivatives. Tetrahedron 2003, 59, 9537-46. 242 Emori, E.; Arai, T.; Sasai, H.; Shibasaki, M. A catalytic Michael addition of thiols to α,β-unsaturated carbonyl compounds: asymmetric Michael additions and asymmetric protonations. J Am Chem Soc 1998, 120, 4043-4.

96

shown with Candida antarctica lipase B.243 Suprisingly, aqueous sodium dodecyl sulfate

solutions perform as powerful catalysts of the Michael additions of thiols or amines to

enones.244 Firouzabadi et al. proposed that the accelerating effect of the sodium dodecyl

sulfate related to the concentrating of the hydrophobic species into the micellar core.

243 Carlqvist, P.; Svedendahl, M.; Branneby, C.; Hult, K.; Brinck, T.; Berglund, P. Exploring the active-site of a rationally redesigned lipase for catalysis of Michael-type additions. Chem Bio Chem 2005, 6, 331-6. 244 Firouzabadi, H.; Iranpoor, N.; Jafari, A. A. Micellar solution of sodium dodecyl sulfate (SDS) catalyzes facile Michael addition of amines and thiols to α,β-unsaturated ketones in water under neutral conditions. Adv Synth Catal 2005, 347, 655-61.

97

Figure 3.15. Regioselective Michael addition through preferential coordination of substrate

carbonyls with lithium cations, reprinted from Tetrahedron, 59, Kamimura et al. “On the

regioselectivity for the Michael addition of thiols to unsymmetrical fumaric derivatives,”

9537-46, Copyright 2003, with permission from Elsevier.245

245 Kamimura, A.; Murakami, N.; Kawahara, F.; Yokota, K.; Omata, Y.; Matsuura, K.; Oishi, Y.; Morita, R.; Mitsudera, H.; Suzukawa, H.; Kakehi, A.; Shiraic, M.; Okamoto, H. On the regioselectivity for the Michael addition of thiols to unsymmetrical fumaric derivatives. Tetrahedron 2003, 59, 9537-46.

98

3.4 Linear Step Growth Michael Addition Polymerizations

3.4.1 Overview

Significant earlier attention was devoted to linear step growth Michael addition

polymerizations. Polymers that were produced via Michael addition polymerizations have

ranged from segmented elastomers to high-Tg engineering thermoplastics. Both rigid,

amorphous, aromatic systems as well as semicrystalline aliphatic systems were pursued and a

wide variety of monomers were employed. Numerous examples of step growth Michael

addition polymerizations exist, however, a few main classifications exist, outlined in Table 1.

Perhaps the earliest example is poly(amido amine)s, which were synthesized from

bisacrylamides and diamines. A second class of step growth polymers are derived from

bismaleimides and diamines, a type of poly(imido amine) referred to as poly(aspartamide)s in

the literature. Thiol nucleophiles are involved in the synthesis of poly(imido sulfide)s,

which are also based on bismaleimide monomers. Analogous poly(ester sulfide)s and

poly(amino ester)s synthesized from diacrylates are potentially biodegradable due to the

hydrolytic instability of the ester linkages. Poly(amino quinone)s are a unique class of

polymers which possess redox activity246 and serve as anticorrosion coatings on metals.

α,β-unsaturated alkyne esters and ketones also serve as Michael acceptors in some cases and

step growth polymerizations based on amine and thiol nucleophiles were pursued. Finally,

hydrogen transfer polymerization allows the synthesis of polyamides and polyesters from

AB-type Michael addition polymerizations. The high conversion of the Michael addition

246 Phama, M. C.; Hubert, S.; Piro, B.; Maurel, F.; Le Daob, H.; Takenouti, H. Investigations of the redox process of conducting poly(2-methyl-5-amino-1,4-naphthoquinone) (PMANQ) film. Interactions of quinone–amine in the polymer matrix. Syn Met 2004, 140, 183-97.

99

reaction and lack of side reactions are prerequisites for high molecular weight in step growth

polymerizations, which is clearly obtained in numerous subsequent examples.

100

Table 3.1. Step growth polymers derived from Michael addition polymerization.

O

NH

COO-Na+

NH

ON N

n

O

O

HN

HN

CF3

F3Cn

O

O

NCH3

NCH3

O

On

SN

O

O

ON

O

O

SOH

OH

O

O O

O

S O S

n

nm

HN P

O HN N

O

O

N

O

O

n

S

PhO O

Ph

SOH

OH n

Ph

NHO O

Ph

HN

n

N

O

O

CH2 N

O

O

OOH

O

n

CH2

Poly(amido amine) Poly(amino ester) Poly(imido sulfide) Poly(ester sulfide) Poly(aspartamide) Poly(imido ether) Poly(amino quinone) Poly(enone sulfide) Poly(enamine ketone)

101

3.4.2 Poly(amido amine)s

Poly(amido amines) are synthesized through the reaction of secondary diamines with

bisacrylamides at 15 to 60 oC in water for durations of hours to days. Also, primary amines,

which have difunctionality in the Michael addition are employed in poly(amido amine)

synthesis (Figure 3.16). Ferruti et al. synthesized linear poly(amido amine)s from a range of

monomers including piperazine bisacrylamide and N,N’-dimethyl-1,6-hexanediamine.247,248

The poly(amido amine) polymerizations occurred rapidly at room temperature in protic

media such as alcohol and water without catalyst. The rate of the Michael addition

polymerization increased with protic solvents and was less dependent on solvent polarity or

dielectric constant. Generally, these polymerizations do not proceed to high molecular

weight in aprotic solvents. The rate of these polymerizations increased with the basicity of

the secondary diamines, and with lower steric hindrance.249 For instance, polymerization

rates increased in the order: N,N’-diisopropylethylenediamine <

N,N’-dimethylethylenediamine < 2-methylpiperazine < piperazine.

247 Ferruti, P.; Marchisio, M. A.; Duncan, R. Poly(amido-amine)s: biomedical applications. Macromol Rapid Commun 2002, 23, 332-55. 248 Ferruti, P.; Marchisio, M. A.; Barbucci, R. Synthesis, physico-chemical properties and biomedical applications of poly(amido-amine)s. Polymer 1985, 26, 1336-48. 249 Danusso, F.; Ferruti, P. Synthesis of tertiary amine polymers. Polymer 1970, 11, 88-113.

102

O

NH

RNH

O

N

R'

H H

O

NH

RNH

O

N

R'n

O

NH

RNH

O

HN

R'

R"NH

R'

O

NH

RNH

O

NR"

R'

N

R'n

Figure 3.16. Poly(amido amine) synthesis via a) primary and b) secondary amines.

a) b)

103

Numerous variations of poly(amido amine) polymerizations exist. Amino acids may

be copolymerized with bisacrylamides, as long as triethylamine is added to deprotonate the

amino acid zwitterion and an amino acid with low steric bulk is employed. Successful

polymerization occurred with glycine, taurine and β-alanine. Peptide oligomers may also be

used as comonomers as long as the amine terminus is a simple amino acid such as glycine.

Monomers such as divinylsulfones and diacrylates250 can replace bisacrylamides as Michael

acceptors. Segmented poly(amido amine ether)s were derived from PEG bis(piperazine)

monomers.251 Other routes to poly(amido amine)s yield different ordering of amido and

amino functionalities including homopolymerization of protected aminoacrylamides with

in-situ deprotection. Yet another route is the reaction of activated acrylic acid derivatives

with secondary diamines through amidation and the also Michael addition.252 Hydrazine

and alkylated hydrazines were also employed in the synthesis of poly(amido amine)s,

however, if excess bisacrylamide monomer is used, then crosslinking occurs with residual

NH groups along the polymer backbone at long reaction times.253,254 Thermal stability of

aliphatic poly(amido amine)s is fairly low, and thermal decomposition occurs near 200 oC.

Poly(amido phosphine)s are synthesized in a similar manner to poly(amido amine)s, with the

250 Sun, G.; Wu, D.; Liua, Y.; Hea, C.; Chung, T. S.; Goh, S. H. pH-controllable cyclic threading/ dethreading of polypseudorotaxane obtained from cyclodextrins and poly(amino ester). Polymer 2005, 46, 3355-62. 251 Ranucci, E.; Ferruti, P. Block copolymers containing poly(ethylene glycol) and poly(amido-amine) or poly(amido-thioether-amine) segments. Macromolecules 1991, 24, 3747-52. 252 Rusconi, L.; Tanzi, M.; Ferruti, P.; Angiolini, L.; Barbucci, R.; Casolaro, M. Synthesis of tertiary poly(amido-amine)s with amido- and amino-groups randomly arranged along the macromolecular chain. Polymer 1982, 23, 1233-6. 253 Danusso, F.; Ferruti, P. Synthesis of tertiary amine polymers. Polymer 1970, 11, 88-113. 254 Malgesini, B.; Ferruti, P.; Manfredi, A.; Casolaro, M.; Chiellini, F. Synthesis, acid-base properties and preliminary cell compatibility evaluation of amphoteric poly(amido-hydrazine)s. J Bioact Compat Polym 2005, 20, 377-94.

104

exception that free radical inhibitors are employed to prevent radical catalyzed addition of the

phosphines to the bisacrylamides. Poly(amido phosphine)s exhibit greater thermal stability

than poly(amido amines), with decomposition temperatures near 360 oC.

Aliphatic poly(amido amines) often possess crystallinity and are water soluble due to

the presence of tertiary amines in the backbone, which undergo partial protonation in water.

Poly(amido amine)s exhibit a tendency toward amide hydrolysis. Ferruti et al. demonstrated

increased solution viscosity versus time during polymerizations at high temperatures (100 oC)

in water, with a subsequent decrease in viscosity at later times. This attribute along with

low toxicity of the amino acid degradation products enables poly(amido amine)s as

degradable pro-drug conjugates.255 Poly(amido amine)s based on hydrazine were found to

decrease in molecular weight by a factor of four over 2 d in water at physiological conditions,

and were also found to possess low cytotoxicity.256

Linear and crosslinked poly(amido amine)s were found to complex with heparin, an

anticoagulant in the human body.257 In medical practice, when heparin levels are too high in

the body, protamine sulfate is administered, which is also an anticoagulant. A solution to

this problem is the use of linear or crosslinked poly(amido amine)s to remove heparin from

the blood stream. Poly(amido amine)s selectively remove heparin over other plasma

components and do not cause hemolysis or affect other properties of blood such as

255 Ferruti, P.; Ranucci, E.; Sartore, L.; Bignotti, F.; Marchisio, M. A.; Bianciardi, P.; Veronese, F. M. Recent results on functional polymers and macromonomers of interest as biomaterials or for biomaterial modification. Biomaterials 1994, 15, 1235-41. 256 Malgesini, B.; Ferruti, P.; Manfredi, A.; Casolaro, M.; Chiellini, F. Synthesis, acid-base properties and preliminary cell compatibility evaluation of amphoteric poly(amido-hydrazine)s. J Bioact Compat Polym 2005, 20, 377-94. 257 Ferruti, P.; Marchisio, M. A.; Duncan, R. Poly(amido-amine)s: biomedical applications. Macromol Rapid Commun 2002, 23, 332-55.

105

prothrombin time. The poly(amido amine)s were also recycled through removal of heparin

upon treatment with alkaline solutions of pH 11. Heparin, when coated on

non-physiological objects, reduces the thrombus formation response of the human body.

Thus, poly(amido amine)s also find utility in creating non-thrombogenic surfaces through

covalent attachment to surfaces. Ferruti et al. developed synthetic methods for surface

attachment of poly(amido amine)s to Dacron™ and poly(vinyl chloride) (PVC) using

Michael addition of terminal acrylamide groups with surface tethered amine groups.258

These surfaces readily adsorbed heparin without heparin release.

Ferruti et al. reacted ethylene sulfide with piperazine to yield dithiol monomers which

were polymerized with bisacrylamides. The resultant polymers were quaternized with

methyl iodide, yielding water soluble antimicrobial polyelectrolytes.259 These polymers

exhibited antimicrobial activity even against resistant strains such as Pseudomonas

aeruginosa. The polymers also possessed surprisingly low rates of hemolysis relative to

commercial antimicrobial polymers.

Ferruti et al. investigated further biomedical applications of poly(amido amine)s in

creating platinum (II) complexes with antitumor activity.260 Polymer-drug conjugates have

improved the effectiveness of drugs through a combination of increased solubility and slow

drug release. The net result is called the enhanced permeability and retention (EPR) effect.

258 Ferruti, P.; Marchisio, M. A.; Barbucci, R. Synthesis, physico-chemical properties and biomedical applications of poly(amido-amine)s. Polymer 1985, 26, 1336-48. 259 Ferruti, P.; Ranucci, E.; Sartore, L.; Bignotti, F.; Marchisio, M. A.; Bianciardi, P.; Veronese, F. M. Recent results on functional polymers and macromonomers of interest as biomaterials or for biomaterial modification. Biomaterials 1994, 15, 1235-41. 260 Ferruti, P.; Ranucci, E.; Trotta, F.; Gianasi, E.; Evagorou, E.; Wasil, M.; Wilson, G.; Duncan, R. Synthesis, characterization and antitumor activity of platinum (II) complexes of novel functionalized poly(amido amine)s. Macromol Chem Phys 1999, 200, 1644-54.

106

Linear poly(amido amine)s based on 2-methylpiperazine, carboxylated bisacrylamides, and

amino-β-cyclodextrin moieties were complexed directly with cisplatin. The degree of

cisplatin complexation and release rate of platinum increased for polymers containing the

cyclodextrin moiety. Release was suppressed however, with the carboxylated bisacrylamide,

and non-carboxylated bisacrylamides were also studied. Both in-vivo and in-vitro toxicity

of most complexes were lower than pure cisplatin, and similar antitumor activities were

observed. Earlier work on poly(amido amine)s revealed effectiveness in reducing tumor

metastasis in Lewis lung tumors and Sarcoma 180 carcinoma implanted in mice.261 The

reduction in cancer metastasis was attributed to specific interactions of these charged

polymers with cell membranes. Neuse et al. also studied poly(amido amine) complexes of

cisplatin, using 1,2-dihydroxylated, 1,2-dicarboxylated or 1-hydroxy-2-carboxyl functional

amine monomers that chelate to the platinum center.262

Recently, Ferruti et al. devoted considerable effort to studying the delivery of genes and

proteins via complexation with poly(amido amine)s. One advantage of poly(amido amine)s

is rapid protonation and expansion at low pH inside tumor cells which releases the genes or

proteins and a compact geometry at plasma pH 7.4 to effectively hold the desired agent prior

to delivery. Small angle neutron scattering (SANS) studies revealed that decreasing the pH

of aqueous poly(amido amine)s solutions increases the radius of gyration from ~2 nm to 8

261 Ferruti, P.; Danusso, F.; Franchi, G.; Polentarutti, N.; Garattini, S. Effects of a series of new synthetic high polymers on cancer metastases? J Med Chem 1973, 16, 496-9. 262 Johnson, M. T.; Komane, L. L.; N'Da, D. D.; Neuse, E. W. Polymeric drug carriers functionalized with pairwise arranged hydroxyl and/or carboxyl groups for platinum chelation. J Appl Polym Sci 2005, 96, 10-19.

107

nm. 263 Furthermore, poly(amido amine)s possess dramatically lower toxicity than

conventional non-viral vectors such as poly(ethylene imine). In some cases, poly(amido

amine)s were prepared that exhibited a “stealth” behavior and maintained long circulatory

lifetimes. 264 Duncan et al. recently investigated poly(amido amine)s that contained

covalently bound endosomolytic protein melittin (a main component of bee venom).265

These conjugates were less toxic than pure melittin and were found to possess pH-selective

hemolytic properties at pH 5.5 and not at pH 7.4 at low concentrations of the conjugates.

Some of the conjugates were also effective in delivering the non-permeant toxin gelonin into

cells. Segmented copolymers based on poly(amido amine)s containing carboxylic acid and

hydroxyl functional blocks also showed promising endosomolytic and gelonin delivery

activity. 266 Gene transfection studies of poly(amido amine)s have also demonstrated

successful polyplex formation with λ Hind III DNA and transfection of β-galactosidase into

HepG2 cells, with similar transfection efficiency as Lipofectin® and poly(ethylene imine).267

Ferruti et al. coupled bovine serum albumin and human serum albumin to poly(amido

amine)s based on piperazine and piperazine bisacrylamide through Michael addition of

263 Griffiths, P. C.; Paul, A.; Khayat, Z.; Wan, K. W.; King, S. M.; Grillo, I.; Schweins, R.; Ferruti, P.; Franchini, J.; Duncan, R. Understanding the mechanism of action of poly(amidoamine)s as endosomolytic polymers: correlation of physicochemical and biological properties. Biomacromolecules 2004, 5, 1422-7. 264 Richardson, S.; Ferruti, P.; Duncan, R. Poly(amidoamine)s as potential endosomolytic polymers: evaluation in vitro and body distribution in normal and tumour-bearing animals. J Drug Target 1999, 6, 391-404. 265 Lavignac, N.; Lazenby, M.; Franchini, J.; Ferruti, P.; Duncan, R. Synthesis and preliminary evaluation of poly(amidoamine)–melittin conjugates as endosomolytic polymers and/or potential anticancer therapeutics. Int J Pharmaceutics 2005, 300, 102-12. 266 Lavignac, N.; Lazenby, M.; Foka, P.; Malgesini, B.; Verpilio, I.; Ferruti, P.; Duncan, R. Synthesis and endosomolytic properties of poly(amidoamine) block copolymers. Macromol Biosci 2004, 4, 922-9. 267 Richardson, S. C. W.; Pattrick, N. G.; Stella Man, Y. K.; Ferruti, P.; Duncan, R. Poly(amidoamine)s as potential nonviral vectors: ability to form interpolyelectrolyte complexes and to mediate transfection in vitro. Biomacromolecules 2001, 2, 1023-8.

108

protein amine groups to terminal acrylamide groups on the poly(amido amine)s.268 The

reaction was conducted under mild conditions (pH 8 to 8.5, 25 oC) to high conversion and the

coupled product was verified by size exclusion chromatography (SEC).

Poly(amino ester)s are similar to poly(amido amine)s, however, they utilize diacrylates

instead of bisacrylamides. Langer et al. studied the use of Michael addition step growth

linear poly(amino ester)s as gene transfection agents (Figure 3.17).269 Like poly(amido

amine)s, poly(amino ester)s have benefits over conventional gene transfection agents (such as

poly(ethylene imine) or poly(L-lysine)) due to their low cytotoxicity as well as

biodegradability into low toxicity byproducts. Furthermore, the structure and degradability

of the poly(amino ester)s are tailored through the incorporation of a wide range of diamines

and diacrylates. Langer et al. obtained high molecular weight poly(amino ester)s (32000

g/mol) and performed successful complexation with plasmid DNA. The absence of a

retro-Michael addition in these systems eliminates the possibility of carcinogenic diacrylate

production during degradation. The degradability of these transfection agents is expected to

aid in the release of the DNA inside the cell.

Non-biological applications of poly(amido amine)s also exist. Recently, Ferruti et al.

examined the introduction of NLO chromophores into both linear and crosslinked poly(amido

amine)s.270 The Michael addition chemistry was well-suited to the primary amine containing

268 Ranucci, E.; Bignotti, F.; Paderno, P. L.; Ferruti, P. Modification of albumins by grafting poly(amido amine) chains. Polymer 1995, 36, 2989-94. 269 Lynn, D. M.; Langer, R. Degradable poly(β-amino esters): synthesis, characterization, and self-assembly with plasmid DNA. J Am Chem Soc 2000, 122, 10761-8. 270 Abbotto, A.; Beverina, L.; Chirico, G.; Facchetti, A.; Ferruti, P. G., M; Pagani, G. A. Crosslinked poly(amido-amine)s as superior matrices for chemical incorporation of highly efficient organic nonlinear optical dyes. Macromol Rapid Commun 2003, 24, 397-402.

109

chromophores and mild reaction conditions prevented chromophore degradation.271 Initial

studies showed that solution optical properties of the chromophores such as two photon

pumped fluorescence were maintained in the polymer.

271 Abbotto, A.; Beverina, L.; Chirico, G. F., A; Ferruti, P.; Pagani, G. A. Design and synthesis of new functional polymers for nonlinear optical applications. Syn Met 2003, 139, 629-32.

110

O

O

O

O NHHN

O

O

O

ONN

n50oC THF

Figure 3.17. Poly(amino ester) synthesis from butanediol diacrylate and piperazine.

111

3.4.3 Poly(imido sulfide)s

Maleimides possess two carbonyl groups conjugated to the double bond, presenting a

highly electron poor double bond susceptible to reaction with a range of nucleophiles.

Poly(imido sulfide)s result from the step growth polymerization of dithiols with bismaleimide

monomers. White and Scaia polymerized aromatic dithiols with aromatic bismaleimides in

m-cresol with catalytic amounts of tri-n-butylamine at 80 to 100 oC.272 The acidity of the

m-cresol prevented the anionic homopolymerization of the maleimide groups upon reaction

with thiolate anions, which would have resulted in crosslinking. The poly(imido sulfide)s

containing aromatic thiol units were susceptible to degradation from bases such as

diethylamine in aprotic solvents which was attributed to retro-Michael addition regeneration

of the maleimide group. Aliphatic dithiol-containing polymers were less susceptible to

depolymerization. Poly(imido sulfide)s with molecular weights ranging from 70000 to

450000 g/mol possessed glass transition temperatures from 185 to 212 oC. Semicrystalline

poly(imido sulfide)s were produced through the reaction of aliphatic dithiols with aliphatic

bismaleimides. 273 Melting temperatures of approximately 77 oC were observed.

Semicrystalline poly(imido sulfide)s possessed stresses at break near 12 MPa and elongations

of 120%. Thermal decomposition of the poly(imido sulfide)s occurred between 336 to 380

oC, and likely resulted from a retro-Michael addition depolymerization. Hydrogen sulfide

serves as an effective dithiol in the synthesis of poly(imido sulfide)s and reacts very rapidly

with bismaleimides in the presence of catalytic quantities of amines such as

272 White, J. E.; Scaia, M. D. Polymerization of N,N’-bismaleimido-4,4’-diphenylmethane with arenedithiols. Synthesis of some new polyimidosulphides. Polymer 1984, 25, 850-4. 273 White, J. E.; Scaia, M. D. Synthesis and properties of some new polyimidosulfides with highly mobile backbones. J Polym Sci: Polym Chem Edn 1984, 22, 589-96.

112

N,N,N’,N’-tetramethylethylenediamine (TMEDA) or acids such as acetic acid (Figure

3.18).274 Poly(imido sulfide)s were also attained from biscitraconimides (methyl substituted

maleimides), which resulted in geminal substitution of the sulfide group on the maleimide

ring at the same position as the methyl group.275

274 Crivello, J. V. Polyimidothioethers. J Polym Sci: Polym Chem Edn 1976, 14, 159-82. 275 Giana, C.; Giana, V. Synthesis of new polyimidosulfides by Michael addition of bis(1-mercapto-2-ethylether) and amido thiosulfide oligomers. Des Mon Polym 2005, 8, 145-58.

113

NN

O

O

O

O

H2SNN

O

O

O

O

S

nDMF/AcOH

25oC

Figure 3.18. Poly(imido sulfide) synthesis from a bismaleimide precursor and hydrogen

sulfide gas.

114

Segmented polymers based on poly(imido sulfide) chemistry were developed by

Crivello and Juliano.276 These polymers were synthesized in an analogous fashion to

polyurethanes, starting with an oligomeric “soft block” consisting of a thiol terminated

polysulfide (Thiokol™ resin) and reacting with an excess of aromatic bismaleimide monomer

in cresol with tri-n-butylamine catalyst at room temperature. The reactive oligomer is chain

extended through reaction with hydrogen sulfide to produce the poly(imido sulfide) “hard

block”. The poor thermal stability of the polysulfide oligomers limited the processing

temperature of the polymers to less than 150 oC, but tensile strengths as high as 10 MPa and

500% elongation were obtained. The thermal instability limited the choice of bismaleimide

monomer to maintain a Tg that was less than 100 oC. These segmented poly(imido sulfide)s

exhibited two glass transition temperatures in dynamic mechanical analysis, indicating the

presence of microphase separation. The rubbery plateau (service window) ranged from -30

to 130 oC. Increasing the hard segment content above 30 wt% led to higher tensile strengths

with lower extensibilities and poor processability. The polysulfide containing segmented

elastomers benefited from excellent solvent resistance.

Dix et al. showed that changing between protic and aprotic monomers in aprotic

solvents controlled the topology of poly(imido sulfide)s (Figure 3.19).277 Bismaleimides

were reacted with oligomeric dithiols as well as low molar mass dithiols in the presence of

catalytic quantities of triethylamine. Oligomeric bisthiols reacted with

276 Crivello, J. V.; Juliano, P. C. Polyimidothioether-polysulfide block polymers. J Polym Sci: Polym Chem Edn 1975, 13, 1819-42. 277 Dix, L. R.; Ebdon, J. R.; Hodge, P. Chain extension and crosslinking of telechelic oligomers-II. Michael additions of bisthiols to bismaleimides, bismaleates and bis(acetylene ketone)s to give linear and crosslinked polymers. Eur Polym J 1995, 31, 653-8.

115

N’,N’-bismaleimido-4,4’-diphenylmethane to create crosslinked networks due to the reaction

of the carbanion formed upon Michael addition with additional maleimide groups. The use

of a protic small molecule dithiol monomer, dithiothreitol, resulted in linear polymers without

crosslinking, due to protonation of the carbanions by hydroxyl groups on dithiothreitol.

Triethylamine does not initiate maleimide polymerization, but deprotonates thiols which are

capable of polymerizing maleimides. For example, an oligomeric dithiol was reacted with

excess monofunctional maleimide in the presence of triethylamine resulting in anionic

polymerization of the maleimide from the chain ends of the oligomeric dithiol.

116

HS SH

OH

OH

O

NN

O

O O

O

O

NN

O

O O

O

SSOH

OH

+

HS O O S S O O SH

O

NNO

O O

O+

S

O

NNO

O O

OS N

O

O

Figure 3.19. a) A typical poly(imido sulfide)s synthesis. b) Possible crosslinking side reaction

through maleimide homopolymerization observed for aprotic oligomeric dithiols.

a)

b)

117

The acrylic analog to poly(imido sulfide)s, poly(ester sulfide)s, were synthesized using

PEG dithiol and butanediol diacrylate or PEG diacrylate using triethylamine base catalyst.278

Varying the length of the PEG spacer enabled hydrophilicity control. The reaction kinetics

were studied in a number of aprotic solvents and increased in the order benzene < dioxane <<

chloroform with increasing dielectric constant. Weight average molecular weights ranged

from 5000 to 28000 g/mol and glass transition temperatures from -50 to -60 oC were

observed. Crystallinity was observed in selected poly(ester sulfide)s.

3.4.4 Poly(aspartamide)s

Poly(aspartamide)s are a class of condensation polymers derived from bismaleimides

and diamine monomers. Poly(aspartamide)s exhibit properties similar to polyimides yet

benefit from a facile, one-pot synthesis and increased solubility in organic solvents relative to

aromatic polyimides and polyamides.279 Poly(aspartamide) synthesis relies on a facile

Michael addition of the amine functional group to the maleimide double bond and does not

require a high temperature poly(amic acid) cyclization reaction as for polyimides.

Crivello synthesized poly(aspartamide)s through the reaction of aromatic diamines with

aromatic bismaleimides in cresol at 110 ºC for 3 d with catalytic amounts of acetic acid.280

The lower basicity of the aromatic amines allowed the use of acetic acid, which activated the

278 Tomasi, S.; Bizzarri, R.; Solaro, R.; Chiellini, E. Poly(ester-sulfide)s from oligo(oxyethylene)dithiols and bis(acrylates). J Bioact Compat Polym 2002, 17, 3-21. 279 Wu, C. S.; Liu, Y. L.; Chiu, Y. S. Synthesis and characterization of new organosoluble polyaspartamides containing phosphorus. Polymer 2002, 43, 1773-9. 280 Crivello, J. V. Polyaspartamides: condensation of aromatic diamines and bismaleimide compounds. J Polym Sci: Polym Chem Edn 1973, 11, 1185-200.

118

maleimide group, through protonation. 281 Model reactions suggested that the

polymerization mechanism involved charged intermediates due to increased rates in polar

solvents. The poly(aspartamide)s exhibited glass transition temperatures near 210 ºC and

thermal decomposition temperatures near 350 ºC. This decomposition occurred at the same

temperature (TGA) in both air and nitrogen atmospheres, suggesting that depolymerization

occurred rather than oxidation. The poly(aspartamide)s possessed tensile strengths near 95

MPa and elongations of 5.5%. Flexural strengths and moduli as high as 140 MPa and 3.1

GPa, respectively, were reported.

Liaw studied poly(aspartamide)s based on arylene ether diamines with improved

thermal stability and 10% weight loss temperatures near 400 ºC (Figure 3.20).282 The

molecular weight of the poly(aspartamide)s increased with increasing monomer

concentration, from Mn = 7,900 at 0.38 M to Mn = 12,800 at 1.0 M. Weight average

molecular weights ranged from 24000 to 68000 g/mol.

281 White, J. E.; Snider, D. A. Reactions of diaminoalkanes with bismaleimides: synthesis of some unusual polyimides. J Appl Polym Sci 1984, 29, 891-9. 282 Liaw, D. J.; Liaw, B. Y.; Chen, J. J. Synthesis and characterization of new soluble polyaspartimides derived from bis(3-ethyl-5-methyl-4-maleimidophenyl)methane and various diamines. Polymer 2001, 42, 867-72.

119

HN

HN

N

O

O

N

O

O

nCH2O

CF3

CF3

O

H2N NH2 N

O

O

N

O

O

CH2O

CF3

CF3

O

Acetic acidm-cresol

Figure 3.20. Thermally stable poly(aspartamide)s synthesized from arylene ether diamines.

120

White and Scaia synthesized amorphous elastomeric poly(aspartamide)s via the

polymerization of aliphatic secondary diamines and aliphatic bismaleimides.283 Acetic acid

was used in the polymerization of aromatic diamines and bismaleimides but not with

aliphatic diamines due to the tendency to protonate the amine groups and prevent

polymerization. The poly(aspartamide)s undergo slow crosslinking at ambient conditions

likely due to Michael addition reaction of amine and maleimide end groups and subsequent

homopolymerization of the maleimide group. Amorphous poly(aspartamide)s possessed

elongations of 1700%, stresses at break near 9.3 MPa, and glass transition temperatures

ranging from 0 to 86 ºC.

Poly(aspartamide)s have potential application in second order non-linear optical (NLO)

materials due to their high glass transition temperatures (~260 to 290 ºC) which help maintain

the critical orientation of the NLO chromophores. In addition, poly(aspartamide)s do not

exhibit poling interferences due to water evolution as seen with polyimides during cyclization

of the precursor poly(amic acid). Wu et al. used Michael addition to obtain an

NLO-containing poly(aspartamide) pre-polymer with maleimide end groups that was

thermally cured to obtain the final product.284 At higher curing temperatures, the glass

transition temperature of the cured poly(aspartamide)s appeared to increase, which

demonstrated that curing continued to 250 ºC.

Poly(amide aspartamide)s are similar to poly(aspartamide)s with the exception that

283 White, J. E.; Scaia, M. D. Synthesis and properties of some new polyimidosulfides with highly mobile backbones. J Polym Sci: Polym Chem Edn 1984, 22, 589-96. 284 Wu, W.; Wang, D.; Zhu, P.; Wang, P.; Ye, C. Thermally stable second-order nonlinear optical addition-type polyimides functionalized by diamine chromophore. J Polym Sci Part A: Polym Chem 1999, 37, 3598–605.

121

polymerization occurs via both Michael addition of amines and maleimides and amidation

reactions of amines and carboxylic acids.285 Poly(amide aspartamide)s are synthesized

through a step growth polymerization of an AA’ monomer containing a carboxylic acid and a

maleimide functional group with a B2 diamine monomer such as those shown in Figure 3.21.

The polymers are thus synthesized in a sequential process beginning with the Michael

addition of the nucleophilic amine groups to the maleimide group followed by the amidation

at the carboxylic acid. These polymers are controllably branched through the addition of

AB2 monomers. One drawback of the poly(amide aspartamide)s is their relatively low

thermal stability, with typical thermal degradation temperatures of 300 to 360 ºC at 10%

weight loss. The char yields of the polymers increased on end-capping the carboxylic acid

end groups with aniline.

285 Wu, C. S.; Tsai, S. H.; Liu, Y. L. One-pot synthesis of linear and branched poly(amide aspartimide)s with good solubility in organic solvents. J Polym Sci Part A: Polym Chem 2005, 43, 1923-9.

122

CH2H2N NH2

O

HON

O

O

CH2HN

HN

ON

O

O n

1) DMAc, 100oC2) TPP, CaCl2, 100oC

Figure 3.21. Typical poly(amide aspartamide) polymerization. The first heating step produces

the Michael adduct while the second step promotes amide bond formation.

123

Oxygen nucleophiles are also effective in step growth polymerizations with

bismaleimides. Hulubei and Rusu copolymerized glycerol and phenolphthalein with aliphatic

bismaleimides resulting in poly(imido ethers).286 The reaction was performed in NMP using

triethylamine or 2-mercaptobenzothiazole as catalysts at 85 to 115 ºC for 2 to 3 d. In the

case of glycerol, the difference in reactivity of the secondary and primary alcohols allowed

synthesis of pendant hydroxyl polymers. Thermogravimetric analysis revealed initial

weight losses ranging from 215 to 400 ºC. Polymerization of bismaleimides with phenols

was successful in solution (95 to 110 ºC) and in the melt (180 ºC), and fiber-glass reinforced

composites were prepared.287

3.4.5 Poly(amino quinone)s

Poly(amino quinone)s are synthesized from primary diamines and quinone, through

Michael additions on both sides of the quinone (Figure 3.22).288 The unsaturated nature of

the quinone is maintained in the polymer, using either excess quinone or other oxidizing

agents. Use of peracetic acid leads to improved yields and simplified purification.

Poly(amino quinone)s have recently found application in anticorrosion coatings and moisture

resistant adhesives. Numerous traditional adhesives suffer from delamination from solid

surfaces in the presence of water. This is due to a stronger interaction of water with the

surface.

286 Hulubei, C.; Rusu, E. New functional poly(bismaleimide-ether)s: synthesis and characterization. Polym Plast Technol Eng 2001, 40, 117-31. 287 Taranu, V.; Pecincu, S. Preparation and properties of poly(bismaleimide ethers). Macromol Reports 1994, A31, 45-52. 288 Vaccaro, E.; Scola, D. A. New applications of polyaminoquinones. CHEMTECH 1999, 29, 15-23.

124

O

O

HN

HN

CF3

F3C

n

O

O

H2N NH2

CF3

F3C

Peracetic acid

Figure 3.22. Poly(amino quinone) synthesis involving peracetic acid as an oxidizing agent.

125

Poly(amino quinone)s, however, displace water on metal surfaces and bind

preferentially. The strong interaction of these polymers with metal surfaces is thought to

arise from the electron donating capabilities of the quinone group. Poly(amino quinone)s

inhibit corrosion on stainless steel surfaces even in the presence of sulfuric acid, through the

formation of a protective coating that forms spontaneously on the metal surface. These

corrosion inhibiting coatings are used for ship hull protection as well as protection of

magnetic particles on data storage media. Diamino quinone containing polyimides are used

to improve the corrosion resistance of interlayer dielectrics in microelectronics. 289

Poly(amino quinone)s have also been introduced into polyolefins and polyurethanes.

Similar to poly(amino quinone)s are poly(thiophenylene)s formed from aromatic

dithiols and bis(1,4-phenylenediimine)s, depicted in Figure 3.23. The product of the

Michael addition between the thiol groups and this nitrogen analog to quinone aromatizes

through proton transfer to the imine nitrogens resulting in a poly(thiophenylene) with pendant

amino groups.290 The polymerization proceeds without a catalyst. These polymers exhibit

electroresponsive behavior and are redox active under acidic conditions. The number

average molecular weight of the polymer was 5,400 g/mol and the glass transition

temperature was 131 oC.

289 Han, M.; Bie, H.; Nikles, D. E.; Warren, G. W. Amine–quinone polyimide: a new high-temperature polymer and its use to protect iron against corrosion. J Polym Sci Part A: Polym Chem 2000, 38, 2893-9. 290 Yamamoto, K.; Higuchi, M.; Takai, H.; Nishiumi, T. Novel synthesis of electroresponsive poly(thiophenylene) through a Michael-type addition. Org Lett 2001, 3, 131-4.

126

S S S

NPh

PhN

NPh

PhN

HS S SH

S

NHPh

PhHN

S S

n

CH2Cl2,RT

Figure 3.23. Polymerization of poly(thiophenylene)s via Michael addition and oxidation.

127

3.4.6 Step Growth Polymers Derived from Bisacetylene-Containing Monomers

Numerous step growth Michael addition polymers are synthesized from bisacetylenic

precursors. The acetylene bond reacts electrophilically when conjugated to electron

withdrawing groups, in a similar fashion to an olefin as noted earlier. Typical functional

groups that serve as Michael receptors are conjugated acetylene ketones and conjugated

acetylene esters. These carbon-carbon triple bond Michael acceptors react with oxygen,

sulfur and amine nucleophiles and adducts possess the additional feature of stereochemistry

at the double bond.291 Michael addition polymers based on acetylenic precursors possess

surprising thermal stability and produce remarkably tough thermoplastics.

Sinsky et al. studied poly(enamine ketone)s synthesized through the Michael addition

reaction of aromatic diamines with aromatic bis(alkynone)s.292 These nucleophilic additions

to acetylenic compounds result primarily in Z isomer formation. The reactions were

performed in m-cresol at 100 oC without catalyst. Glass transition temperatures between

198 and 235 oC were obtained and thermogravimetric decomposition temperatures were

nearly 300 oC. The poly(enamine ketone)s were tough thermoplastics, with tensile strengths

of 85 MPa (63 MPa at 93 oC), tensile moduli of 2.27 GPa, and elongations of 4%.

Bass et al. synthesized poly(enone sulfide)s, the sulfur analog to poly(enamine ketone)s

through the reaction of aromatic dithiols (e.g. 1,3-benzenedithiol) with aromatic internal

bis(alkynone)s in m-cresol at room temperature with N-methyl morpholine as a catalyst at

291 Dickstein, J. I.; Miller, S. I., Nucleophilic attacks on acetylenes. In The chemistry of the carbon-carbon triple bond. Part 2, Patai, S., Ed. Wiley: New York, 1978; pp 813-955. 292 Sinsky, M. S.; Bass, R. G.; Connell, J. W. Poly(enamine ketones) from aromatic diacetylenic diketones and aromatic diamines. J Polym Sci Part A: Polym Chem 1986, 24, 2279-95.

128

temperatures from 25 to 40 oC.293 The polymers had moderately high glass transition

temperatures (Tg ~ 107 to 156 oC) and thermal decomposition temperatures near 330 oC.

Tough, clear films were obtained from solution casting and exhibited tensile strengths of 78

MPa and tensile moduli near 3.2 GPa. Dix et al. also synthesized poly(enone sulfide)s from

internal bis(alkynone)s and found a Z:E ratio of 60/40 (Figure 3.24).294 Model reactions of

thiols with phenylacetylene resulted in almost exclusive formation of the Z isomer.295

3.4.7 Hydrogen transfer polymerization

Nylon-3 type polyamides are also synthesized via a Michael addition process. The

base catalyzed polymerization of acrylamide to poly(β-alanine), as shown in Figure 3.25, was

originally proposed as an anionic chain growth process, which occurred with proton transfer

of the amide NH2 on the growing chain end to the enolate carbanion. This process was

described as a “hydrogen transfer polymerization.” However, it was later classified as a step

growth polymerization due to proton transfer from the growing enolate carbanion to amide

NH2 groups on other monomers. Bush and Breslow demonstrated this via monitoring

molecular weight as a function of monomer conversion.296 At very short reaction times, high

monomer conversion was achieved but high molecular weight product was not obtained

293 Bass, R. G.; Cooper, E.; Hergenrother, P. M.; Connell, J. W. Poly(enone sulfides) from the addition of aromatic dithiols to aromatic dipropynones. J Polym Sci Part A: Polym Chem 1987, 25, 2395-407. 294 Dix, L. R.; Ebdon, J. R.; Hodge, P. Chain extension and crosslinking of telechelic oligomers-II. Michael additions of bisthiols to bismaleimides, bismaleates and bis(acetylene ketone)s to give linear and crosslinked polymers. Eur Polym J 1995, 31, 653-8. 295 Truce, W. E.; Simms, J. A. Stereospecific reactions of nucleophilic agents with acetylenes and vinyl-type halides. IV. The stereochemistry of nucleophilic additions of thiols to acetylenic hydrocarbons. J Am Chem Soc 1956, 78, 2756-9. 296 Bush, L. W.; Breslow, D. S. The mechanism of hydrogen transfer polymerization. Macromolecules 1968, 1, 189-90.

129

suggesting initial dimerization and trimerization. Longer reaction times led to high

molecular weight poly(β-alanine). These polymerizations were typically conducted at 80 to

120 oC in aprotic solvents such as DMF in the presence of radical inhibitors. Further work

from Lim et al. demonstrated that branching occurred in these polymerizations in aprotic

solvents due to propagation of both enolate and amide anions, which are formed before and

after hydrogen transfer, respectively.297

297 Camino, G.; Lim, S. L.; Trossarelli, L. Branching in the base catalyzed hydrogen transfer polymerization of acrylamide in N-methyl-2-pyrrolidone at 100oC. Eur Polym J 1977, 13, 479-81.

130

S

PhO O

Ph

S

OH

OH nPh

O O

Ph

HS SH

OH

OH

cat. Et3N

CH2Cl2

Figure 3.24. Poly(enone sulfide) synthesis via Michael addition step growth.

131

O

NH2

Base

80-120 oC

O

NH

O

NH2n

Figure 3.25. Hydrogen transfer polymerization of acrylamide to poly(β-alanine).

132

Hydrogen transfer polymerization of acrylamide in the presence of carbon black and

n-butyl lithium was effective in grafting of poly(β-alanine) onto the carbon black via

polymerization from surface lithium alkoxides. 298 The grafted carbon black showed

improved dispersability in water and organic solvents, and grafting ratios of 60 to 80% were

achieved. Recently, the hydrogen transfer polymerization process was applied to

N-acetylacrylamide and N-benzoylacrylamide and the proton transfer mechanism was

preserved despite the steric hindrance and lower acidity of the amide NH groups.299

Hydrogen transfer polymerization was also achieved with N-acryloyl-N’-p-tolylureas,300

p-styrenesulfonamides, heterocyclic base containing acrylamides,301 and maleimide.

In a similar nature to the hydrogen transfer polymerization of acrylamide, hydroxyalkyl

acrylates are also polymerizable through Michael addition chemistry as AB monomers. The

polymerization of hydroxyethyl acrylate was performed at temperatures from 85 to 150 oC in

the presence of free radical inhibitors using bases such as sodium hydride and potassium

tert-butoxide as initiators.302 Molecular weights as high as 9000 g/mol were obtained and

hydroxyethyl acrylate polymerized more effectively than hydroxyethyl methacrylate. The

primary side reaction in these polymerizations is the disproportionation of hydroxyethyl

298 Tsubokawa, N.; Nagano, Y.; Sone, Y. Grafting of poly(β-alanine) onto carbon black: The hydrogen transfer polymerization of acrylamide catalyzed by n-butyllithium in the presence of carbon black. J Appl Polym Sci 1984, 29, 985-93. 299 Iwamura, T.; Tomita, I.; Suzuki, M.; Endo, T. Hydrogen-transfer polymerization behavior of N-acylacrylamide. J Polym Sci Part A: Polym Chem 2000, 38, 430-5. 300 Iwamura, T.; Tomita, I.; Suzuki, M.; Endo, T. Hydrogen-transfer polymerization of vinyl monomers derived from p-tolyl isocyanate and acrylamide derivatives. React Funct Polym 1999, 40, 115-22. 301 Kondo, K.; Tanioku, S.; Takemoto, K. Functional monomers and polymers. LI. On the synthesis and polymerization of acryloylaminomethyl derivatives of nucleic acid bases. Polym J 1979, 1, 81-2. 302 Gibas, M.; Korytkowska-Walach, A. Polymerization of 2-hydroxyethyl acrylate and methacrylate via Michael-type addition. Polym Bull 2003, 51, 17-22.

133

acrylate to ethylene glycol diacrylate and ethylene glycol.

3.5 Linear Chain Growth Michael Addition Polymerizations

A classic example of Michael addition polymerization is the anionic chain-growth

polymerization of methacrylate monomers. This review is not intended to comprehensively

review anionic polymerization but rather to place the Michael addition in context for trends in

polymer synthesis strategies. Anionic polymerization has been reviewed extensively in the

literature.303304

- 305 The relatively low reactivity of the methacrylate, as noted earlier, towards

Michael addition chemistry demands a stronger nucleophile, thus carbanionic species such as

diphenylhexyllithium and nitrogen anions such as lithium diisopropyl amide are suitable for

the polymerization of alkyl methacrylates. One current limitation is the requirement for

cryogenic temperatures to prevent potential nucleophilic attack of the enolate anion on ester

groups. Group transfer polymerization, which was developed in the mid-1980s, enabled

polymerization at ambient temperatures due to the use of a reversible silyl protecting group

that was proposed to stabilize the propagating chain end. Anionic polymerization was

demonstrated with acrylamides and acrylate monomers, later, and this may complicate step

growth processes in some cases.306 The polymerization of cyanoacrylates is another chain

303 van Beylen, M.; Bywater, S.; Smets, G.; Swarc, M.; Worsfold, D. J. Developments in anionic polymerization - a critical review. Adv Polym Sci 1988, 86, 87-143. 304 Teyssie, P.; Baran, J.; Dubois, P.; Jerome, R.; Wang, J. S.; Yu, J.; Yu, Y.; Zundel, T. Living anionic polymerization of (meth)acrylic esters. New mechanistic concepts and resulting materials. Macromol Symp 1998, 132, 303-7. 305 Hirao, A.; Hayashi, M. Recent advance in syntheses and applications of well-defined end-functionalized polymers by means of anionic living polymerization. Acta Polymerica 1999, 50, 219-31. 306 Reetz, M. T.; Ostarek, R. Polymerization of acrylic acid esters initiated by tetrabutylammonium alkyl- and aryl- thiolates. J Chem Soc Chem Commun 1988, 3, 213-5.

134

growth Michael addition process. Cyanoacrylates are initiated with very poor nucleophiles,

such as water, due to the electron poor olefin and strong resonance contributions of the

adjacent cyano and ester groups. Cyanoacrylate polymerizations are widely used in rapid

cure adhesives, and adhesive products possessing extremely high bond strengths.

3.5.1. Anionic Polymerization of Methacrylates

Anionic polymerization of alkyl methacrylates is an established chain growth

polymerization technique which relies upon Michael addition chemistry. Anionic

polymerization is known for producing polymers of controlled molecular weights and narrow

polydispersity. Anionic polymerization is particularly suited for well-defined block

copolymers 307 and star-shaped polymers via chain-end coupling strategies. A further

advantage of anionic polymerization is the potential for controlling tacticity, which was

achieved for the sterically bulky tert-butyl methacrylate monomer in toluene by Long et al.308

Anionic polymerization is generally initiated using alkyllithium initiators with sufficient

nucleophilicity to attack alkyl methacrylate monomers. However, due to the potential side

reaction of the carbanionic chain end with ester carbonyls, the reaction must be conducted at

low temperatures and with sterically hindered carbanions such as diphenylhexyllithium.307

These bulky carbanions react selectively at the double bond, resulting in an enolate Michael

adduct, as shown in Figure 3.26.

307 Long, T. E.; Broske, A. D.; Bradley, D. J.; McGrath, J. E. Synthesis and characterization of poly(tert-butyl methacrylate-b-isoprene-b-tert-butyl methacrylate) block copolymers by anionic techniques. J Polym Sci Part A: Polym Chem 1989, 27, 4001-12. 308 Allen, R. D.; Long, T. E.; McGrath, J. E. Synthesis of tactic poly(alkyl methacrylate) homo- and copolymers. Polym Sci Tech 1985, 31, 347-62.

135

CH3

OMeO

Ph

Ph

Bu CH3

O

MeO

R CH3

O

MeO

R

CH3

O

MeO

CH3

O

MeO

R Hn

2) H3O+

THF,-78oC

Figure 3.26. Anionic polymerization of methyl methacrylate from diphenylhexyl lithium.

136

The strong nucleophilicity of the anionic PMMA growing chain end was used in chain

end functionalization strategies in numerous cases.309 For example, addition of di-tert-butyl

maleate at the end of the polymerization results in succinate ester end groups.310 These end

groups were then pyrolyzed to produce reactive anhydrides capable of imide coupling with

amine functional polymers. Long et al. acheived end functionalization with hydrogen

bonding groups via Michael addition of heterocyclic base pairs to acrylated polystyrenes

(Figure 3.27).311 Termination of the anionic polymerization of styrene with ethylene oxide

created hydroxyl functionality which allowed esterification with acryloyl chloride. Michael

addition of nucleotide bases then allowed facile functionalization of the polystyrene chains,

without detracting from hydrogen bonding properties. Adenine and thymine functionalized

polystyrene demonstrated association in 1H NMR spectroscopic investigations.

Long et al.312,313 as well as Muller et al.314 studied the synthesis of diene / acrylic,

styrene / acrylic and all acrylic triblock copolymers containing tert-butyl methacrylate, which

were later hydrolyzed and neutralized to obtain carboxylate block ionomers. The bulkier

309 Hirao, A.; Hayashi, M. Recent advance in syntheses and applications of well-defined end-functionalized polymers by means of anionic living polymerization. Acta Polymerica 1999, 50, 219-31. 310 Cernohous, J. J.; Macosko, C. W.; Hoye, T. R. Anionic synthesis of polymers functionalized with a terminal anhydride group. Macromolecules 1997, 30, 5213-9. 311 Yamauchi, K.; Lizotte, J. R.; Long, T. E. Synthesis and characterization of novel complementary multiple-hydrogen bonded (CMHB) macromolecules via a Michael addition. Macromolecules 2002, 35, 8745-50. 312 Long, T. E.; Broske, A. D.; Bradley, D. J.; McGrath, J. E. Synthesis and characterization of poly(tert-butyl methacrylate-b-isoprene-b-tert-butyl methacrylate) block copolymers by anionic techniques. J Polym Sci Part A: Polym Chem 1989, 27, 4001-12. 313 Deporter, C. D.; Long, T. E.; McGrath, J. E. Methacrylate-based block ionomers. I. Synthesis of block ionomers derived from t-butyl methacrylate and alkyl methacrylates. Polym Int 1994, 33, 205-16. 314 Ludwigs, S.; Boker, A.; Abetz, V.; Muller, A. H. E.; Krausch, G. Phase behavior of linear polystyrene-block-poly(2-vinylpyridine)-block-poly(tert-butyl methacrylate) triblock terpolymers. Polymer 2003, 44, 6815-23.

137

ester alkyl prohibits carbonyl ester attack at room temperature. Long et al. also established

the utility of lithium diisopropylamide (LDA) as an initiator for methacrylate polymerizations

in THF at -78 oC, despite the relatively low nucleophilicity of the hindered amide ion.315

Anionic polymerization of acrylates,316 maleimides, vinyl ketones317 and acrylamides318

are also known.

315 Long, T. E.; Guistina, R. A.; Schell, B. A.; McGrath, J. E. Hindered lithium dialkylamide initiators for the living anionic polymerization of methacrylic esters. J Polym Sci Part A: Polym Chem 1994, 32, 2425-30. 316 Reetz, M. T.; Ostarek, R. Polymerization of acrylic acid esters initiated by tetrabutylammonium alkyl- and aryl- thiolates. J Chem Soc Chem Commun 1988, 3, 213-5. 317 Catterall, E.; Lyons, A. R. Organometal initiated polymerization of vinyl ketones. I. n-Butyllithium initiated polymerization of methyl isopropenyl ketone. Eur Polym J 1971, 7, 839-48. 318 Kodaira, T.; Tanahashi, H.; Hara, K. Cyclopolymerization XVII. Anionic cyclopolymerization tendency of N-methyldiacrylamide and N-substituted dimethacrylamides. Polym J 1990, 22, 649-59.

138

PhBu

OH

Phn

1) s-BuLi

2)

cyclohexaneRT

O

O

Cl

Et3NCHCl3RT

BuO

Phn

O NH

NH

O

O

BuO

Phn

O

N NH

O

O

tBuOKDMSO60oC

+

Figure 3.27. Michael addition of heterocyclic nucleotide bases to acrylated anionic

polystyrene.

139

In some cases, anionically polymerized methacrylates have been designed for

biologically related applications. For instance, Okamoto et al. synthesized macrocyclic

ether containing acrylic monomers which polymerized anionically to obtain highly isotactic

polymers capable of functioning as synthetic ion channels in hexadecyl phosphate vesicles

(Figure 3.28).319 In contrast, radical polymerization of macrocyclic ether monomers yielded

atactic polymer with dramatically lower ion transport.

319 Habaue, S.; Morita, M.; Okamoto, Y. Stereospecific anionic polymerization of α-(hydroxymethyl)acrylate derivatives affording novel vinyl polymers with macrocyclic side chains. Polymer 2002, 43, 3469-74.

140

OO

O

O

O

cyc-hexyl-Mg-BrTMEDA

Figure 3.28. Polymerization of macrocyclic ether acrylic monomers to form ion channels.

Reprinted from Polymer, 43, Okamoto, et al. “Stereospecific anionic polymerization of

α-(hydroxymethyl)acrylate derivatives affording novel vinyl polymers with macrocyclic side

chains,” 3469-74, Copyright 2002, with permission from Elsevier.320

320 Habaue, S.; Morita, M.; Okamoto, Y. Stereospecific anionic polymerization of α-(hydroxymethyl)acrylate derivatives affording novel vinyl polymers with macrocyclic side chains. Polymer 2002, 43, 3469-74.

141

3.5.2 Group Transfer Polymerization

Commonly, anionic polymerization of alkyl methacrylates is conducted at cryogenic

temperatures. Such temperatures are generally not industrially feasible, except in the cationic

polymerization of isobutylene, and significant research effort was directed towards a

methodology that was amenable to higher temperatures. Group transfer polymerization

(GTP) is a polymerization methodology that was developed in the mid-1980s by DuPont as a

method of producing narrow polydispersity methacrylate and acrylate polymers and block

polymers above room temperature.321 GTP is conveniently conducted at 80 oC using a silyl

ketene acetal initiator in the presence of a nucleophilic anionic catalyst (Figure 3.29).

Initially, GTP was believed to proceed through a transfer of a silyl protecting group from the

enolate oxygen on the chain end to monomers during the propagation step.322 This initial

mechanism has largely been disproven in favor of a dissociative anionic polymerization

mechanism which involves a reversible dissociation of the silyl protecting group from the

enolate oxygen, aided by anionic catalysts (HF2-, bibenzoate anion). The position of the

equilibrium between the free enolate and the silyl protected enolate determines the rate of the

polymerization. Similar to anionic polymerizations, the reaction is terminated through the

addition of a protic species such as methanol. GTP is currently used by DuPont to produce

acrylic block copolymers for pigment dispersing applications in automotive paints.321

321 Webster, O. W. Group transfer polymerization: Mechanism and comparison with other methods for controlled polymerization of acrylic monomers. Adv Polym Sci 2004, 167, 1-34. 322 Webster, O. W.; Hertler, W. R.; Sogah, D. Y.; Farnham, W. B.; RajanBabu, T. V. Group-transfer polymerization. 1. A new concept for addition polymerization with organosilicon initiators. J Am Chem Soc 1983, 105, 5706-8.

142

OMe

OSiMe3O

CH3

MeO

+HF2

-

H

OMeO MeO

OSiMe3n

Figure 3.29. Group transfer polymerization of methyl methacrylate.

143

3.5.3 Anionic Polymerization of α-cyanoacrylates

Cyanoacrylates are a class of monomers which undergo rapid anionic polymerization

initiated by weak nucleophiles such as water, as shown in Figure 3.30. These rapidly

polymerizing monomers are used primarily in the adhesives industry as a high strength rapid

setting adhesives. 323 The added electron withdrawing character of the nitrile group

facilitates anionic polymerization of these monomers. Unlike conventional anionic

polymerization, however, molecular weight control is absent. Klemarczyk studied the

polymerization of ethyl cyanoacrylate using phosphine and amine initiators.324 The initiated

monomer species is zwitterionic, which makes it an effective nucleophile towards further

monomer addition. Primary and secondary amines intiate more slowly than tertiary amines

due to proton transfer after the first addition of monomer, which results in a neutral, less

reactive adduct. In terms of current biomedical applications, octyl cyanoacrylate has

recently found application as a tissue adhesive and gained FDA approval for surgical use.325

This monomer polymerizes on contact with a wound and maintains flexibility due to the

pendant octyl chain and furthermore possesses low water solubility.

323 Klemarczyk, P., Cyanoacrylate instant adhesives. In Adhesion Science and Engineering, Dillard, D. A.; Pocius, A. V., Eds. Elsevier: Amsterdam, 2002; pp 847-67. 324 Klemarczyk, P. The isolation of a zwitterionic initiating species for ethyl cyanoacrylate (ECA) polymerization and the identification of the reaction products between 1º, 2º, and 3º amines with ECA. Polymer 2001, 42, 2837-48. 325 Singer, A. J.; Thode, H. C. A review of the literature on octyl cyanoacrylate tissue adhesive. Amer J Surgery 2004, 187, 238-48.

144

CN

O

EtO

CN

O

EtO

HO CN

O

EtO

R

CN

O

EtO

CN

O

EtO

R H

2) H2O

HO

H

n

C

O

EtO

HO

N

Figure 3.30. Water-initiated polymerization of ethyl α-cyanoacrylate.

145

3.5.4 Living Radical Polymerization

Living radical polymerization encompasses several techniques for producing

well-defined homopolymers, block copolymers, and star polymers. Due to the radical

nature of this polymerization methodology, a wider range of monomers are accessible

compared to traditional anionic polymerization and less stringent purification techniques are

required. Numerous living radical polymerization methods are currently known, including

atom transfer radical polymerization (ATRP) which involves activated alkyl halides and

metal catalysts,326 stable free radical polymerization (SFRP) which utilizes nitroxides,327 and

reversible addition fragmentation chain transfer polymerization (RAFT) which typically

utilizes dithioester or dithiocarbamate chain transfer reagents.328 Michael addition reactions

have recently proven useful in many of these living radical polymerization strategies.

Functional initiation is of interest for the synthesis of well-defined polymers with the

potential for block copolymer synthesis, coupling with proteins or reaction with surfaces.

Recently, Michael addition was used to synthesize an ATRP initiator containing two hydroxyl

groups.329 This novel dihydroxyl initiator allowed the synthesis of Y-shaped polymers via a

combination of ATRP on the initial alkyl halide site and post polymerization conversion of

the hydroxyl groups to alkyl halides which allowed polymerization of a second monomer

(Figure 3.31). Matyjaszewksi et al. recently studied the synthesis of ATRP ligands through

326 Matyjaszewski, K.; Xia, J. Atom transfer radical polymerization. Chem Rev 2001, 101, 2921-90. 327 Hawker, C. J.; Bosman, A. W.; Harth, E. New polymer synthesis by nitroxide mediated living radical polymerizations. Chem Rev 2001, 101, 3661-88. 328 Moad, G.; Mayadunne, R. T. A.; Rizzardo, E.; Skidmore, M.; Thang, S. H. Synthesis of novel architectures by radical polymerization with reversible addition fragmentation chain transfer. Macromol Symp 2003, 192, 1-12. 329 Cai, Y.; Armes, S. P. Synthesis of well-defined Y-shaped zwitterionic block copolymers via atom-transfer radical polymerization. Macromolecules 2005, 38, 271-9.

146

the Michael addition reaction of tris(aminoethyl)amine with several acrylates, resulting in

ligands that were suitable for the polymerization of methacrylic, acrylic and styrenic

monomers in nonpolar media.330 Matyjaszewski et al. also synthesized ATRP ligands

containing dimethoxymethylsilylpropyl acrylate, which aided in post-polymerization catalyst

removal via passage through silica gel and coupling of the complexes to the silica gel via

sol-gel reactions. Shen et al. synthesized novel diaminopyridine (DAP) containing ATRP

ligands through acrylation of DAP followed by Michael addition using

bis(diethylaminoethyl)amine. 331 Silica gel modified with thymine residues created

hydrogen bonded associations with these DAP ATRP ligands which dissociated at reaction

temperatures, allowing polymerization to occur. After cooling the reaction, re-association

allowed removal and recycling of the catalyst.

Synthesis of functional polymers is also achieved through post-polymerization

strategies based on the Michael addition. For example, hydroxyl functionalized RAFT

polymerized PMMA were synthesized using hydrolysis of the dithioester end groups

followed by Michael addition with hydroxyethyl acrylate to the thiol group.332

330 Gromada, J.; Spanswick, J.; Matyjaszewski, K. Synthesis and ATRP activity of new TREN-based ligands. Macromol Chem Phys 2004, 205, 551-66. 331 Ding, S.; Yang, J.; Radosz, M.; Shen, Y. Atom transfer radical polymerization of methyl methacrylate via reversibly supported catalysts on silica gel via self-assembly. J Polym Sci Part A: Polym Chem 2004, 42, 22-30. 332 Lima, V.; Jiang, X.; Brokken-Zijp, J.; Schoenmakers, P.; Klumperman, B.; van der Linde, R. Synthesis and characterization of telechelic polymethacrylates via RAFT polymerization J Polym Sci Part A: Polym Chem 2005, 43, 959-73.

147

O

O OH

O

BrBr

1)

2)HN

HO OH

O

O O

O

BrN

HO

HO

HO

HOPolymer A

O

BrBr

O

OPolymer A

O

Br

O

Br

monomer A

monomer BO

OPolymer A

O

B Polymer

O

B Polymer

ATRP

ATRP

Figure 3.31. Synthesis of a dihydroxyl functional ATRP initiator.

148

3.6 Synthesis of Branched Polymers via the Michael Addition Reaction

Branched polymers encompass a wide range of topologies, ranging from hyperbranched

to graft and dendritic polymers. Michael addition polymerization mechanisms were broadly

applied to each of these topological designs. Hyperbranched polymers have gained interest

recently, due to a large number of functional termini and processing advantages in terms of

lower melt viscosity relative to linear polymers of equivalent molecular weight. Michael

addition provides the means to incorporate numerous types of terminal functionalities due to

an inherent functional group tolerance and wide variety of monomers. Graft copolymers are

also of increasing interest given the similarity to block copolymers and the ability to control

the graft density and graft length. Graft copolymers often possess microphase separated

morphologies and offer elastomeric properties. Dendrimers have traditionally been

synthesized using Michael addition reactions, and in fact, Tomalia et al. synthesized the first

dendrimer, poly(amido amine) (PAMAM) using Michael addition. Dendrimers and

hyperbranched polymers, are interesting due to a plurality of functional groups. However,

the absence of entanglements often limits the use of dendrimers to non-structural and

mechanically non-demanding applications. Dendrimers based on Michael addition reactions

are used in numerous applications, including biomedical applications and gene delivery.333,334

333 Bielinska, A.; Kukowska-Latallo, J. F.; Johnson, J.; Tomalia, D. A.; Baker, J. R. Regulation of in vitro gene expression using antisense oligonucleotides or antisense expression plasmids transfected using starburst PAMAM dendrimers. Nuc Acid Res 1996, 24, 2176-82. 334 Kubasiak, L.; Tomalia, D. A., Cationic dendrimers as gene transfection vectors: Dendri-poly(amido amines) and dendri-poly(propyleneimines). In Polymeric Gene Delivery, Amiji, M. M., Ed. CRC Press: Boca Raton, FL, 2005; pp 133-57.

149

3.6.1 Dendrimers

Michael addition reactions are ideal for dendrimer synthesis due to the low probability

of side reactions and mild reaction conditions. In the first dendrimer synthesis, dendritic

poly(amido amine)s were synthesized via the alternating Michael addition of methyl acrylate

to amine substrates (ammonia, f = 3; ethylenediamine, f = 4) and aminolysis of the resultant

esters with excess ethylene diamine.335 As depicted in Figure 3.32, the PAMAM dendrimer

synthesis is divergent, beginning from a small molecule core and enlarging as further

generations are added. The high conversion and facile nature of the Michael addition led to

nearly monodisperse individual dendrimer molecules as revealed using electron

microscopy.336 The Michael addition was most efficient in methanol, while aprotic solvents

led to incomplete alkylation of amine groups. Retro-Michael additions fragmented the

dendrimer molecules at elevated temperature (80 oC) in solution.337

335 Tomalia, D.; Naylor, A. M.; Goddard, W. A. Starburst dendrimers: Molecular-level control of size, shape, surface chemistry. Angew Chem Int Ed 1990, 29, 138-175. 336 Tomalia, D. A.; Baker, H.; Dewald, J.; Hall, M.; Kallos, G.; Martin, S.; Roeck, J.; Ryder, J.; Smith, P. Dendritic macromolecules: Synthesis of starburst dendrimers. Macromolecules 1986, 19, 2466-8. 337 Tomalia, D. A.; Baker, H.; Dewald, J.; Hall, M.; Kallos, G.; Martin, S.; Roeck, J.; Ryder, J.; Smith, P. A new class of polymers: starburst-dendritic macromolecules. Polym J 1985, 17, 117-32.

150

N HHH

NOOMe

OMeO

OMeO

NO

HNONH

OHN

H2N NH2

NH2

NO

HNONH

OHN

N N

N

OMeO

OMeO

OOMe

OOMe

O OMe

OOMe

methyl acrylate ethylene diamine methyl acrylate

Figure 3.32. Divergent PAMAM dendrimer synthesis via alternating Michael addition and

amidation.

151

PAMAM dendrimers are effective gene transfection agents due to the plurality of

terminal amine groups available to complex with the negatively charged DNA phosphate

backbone. In aqueous solution, protonation of the terminal amine groups produces a

cationic charge that favors complexation with DNA. A DNA-polymer complex must have a

net positive charge in order to pass through a cell membrane. The PAMAM dendrimers

effectively transfected genes for β-galactosidase expression, luciferase expression, and also

antisense genes that selectively suppress luciferase genes.338 PAMAM dendrimers received

significant attention for effectiveness in gene transfection and numerous transfection studies

were performed on diverse eukaryotic cell lines. Studies found increased transfection

efficiency for higher generation dendrimers.339 Higher generations were necessary to obtain

efficient coverage of DNA, as higher generations possessed sizes close to the histone octamer.

Heating the dendrimers in aqueous solution led to fragmentation, likely through

retro-Michael additions and solvolysis, which significantly improved transfection. In fact, a

commercial gene transfection agent, Superfectin™, is based on fragmented PAMAM

dendrimers. PAMAM dendrimers of numerous sizes possess very low cytotoxicity and

in-vivo studies have also showed low toxicity.

Amine terminated PAMAM dendrimers were recently used to eliminate prion proteins

from scrapie infected neuroblastoma cells.340 Higher generation PAMAM dendrimers were

338 Bielinska, A.; Kukowska-Latallo, J. F.; Johnson, J.; Tomalia, D. A.; Baker, J. R. Regulation of in vitro gene expression using antisense oligonucleotides or antisense expression plasmids transfected using starburst PAMAM dendrimers. Nuc Acid Res 1996, 24, 2176-82. 339 Kubasiak, L.; Tomalia, D. A., Cationic dendrimers as gene transfection vectors: Dendri-poly(amido amines) and dendri-poly(propyleneimines). In Polymeric Gene Delivery, Amiji, M. M., Ed. CRC Press: Boca Raton, FL, 2005; pp 133-57. 340 Supattapone, S.; Nguyen, H. O. B.; Cohen, F.; Prusiner, S. B.; Scott, M. R. Elimination of prions by branched polyamines and implications for therapeutics. Proc Natl Acad Sci USA 1999, 96, 14529-34.

152

more effective in removing the prion proteins and were most effective below pH 4,

suggesting the importance of ammonium charge and activity in the lysosomal or endosomal

regions. The importance of branching was demonstrated through the comparison of linear

and branched poly(ethylene imine) controls. The ability to remove prions occurred at

noncytotoxic dendrimer concentrations.

A second common dendrimer is poly(propylene imine) (PPI), marketed under the trade

name Astramol™.341 PPI dendrimers are accessed through the Michael addition of primary

diamines with acrylonitrile followed by hydrogenation of the nitrile groups to amines and

repeated reaction with acrylonitrile (Figure 3.33). First through fifth generation dendrimers

are commercially produced in this manner. PPI dendrimers were recently synthesized with

poly(propylene oxide) Jeffamine® cores, allowing greater flexibility and less steric

congestion of the dendrimer molecules.342 The terminal nitrile groups of poly(propylene

imine) dendrimers are hydrolyzed under acidic conditions to obtain peripheral carboxylic

acid functionality, but this often leads to degradation or discoloration of the polymer. Meijer

et al. developed a route to carboxylic acid functional dendrimers via hydrogenation of the

peripheral nitriles followed by the Michael addition of methyl acrylate and basic hydrolysis

of the resultant ester functionalities.343 In contrast to PAMAM dendrimers, PPI dendrimers

341 Froehling, P.; Brackman, J. Properties and applications of poly(propylene imine) dendrimers and poly(ester amide) hyperbranched polymers. Macromol Symp 2000, 151, 581-9. 342 Froimowicz, P.; Gandinib, A.; Strumia, M. New polyfunctional dendritic linear hybrids from terminal amine polyether oligomers (Jeffamine): synthesis and characterization. Tet Lett 2005, 46, 2653-7. 343 van Duijvenbode, R. C.; Rajanayagam, A.; Koper, G. J. M.; Baars, M. W. P. L.; de Waal, B. F. M.; Meijer, E. W.; Borkovec, M. Synthesis and protonation behavior of carboxylate-functionalized poly(propyleneimine) dendrimers. Macromolecules 2000, 33, 46-52.

153

have less potential for gene transfection and higher cytotoxicity.344 Lower toxicity was

achieved with PPI dendrimers containing ether and ester linkages, synthesized by the Michael

addition of alcohols to acrylonitrile, reduction of the nitrile, Michael addition to methyl

acrylate, and reduction back to alcohol terminal groups.345

344 Kubasiak, L.; Tomalia, D. A., Cationic dendrimers as gene transfection vectors: Dendri-poly(amido amines) and dendri-poly(propyleneimines). In Polymeric Gene Delivery, Amiji, M. M., Ed. CRC Press: Boca Raton, FL, 2005; pp 133-57. 345 Krishna, T. R.; Jayaraman, N. Synthesis of poly(propyl ether imine) dendrimers and evaluation of their cytotoxic properties. J Org Chem 2003, 68, 9694-704.

154

NH2H2N

CN

NN

NC

NC

CN

CN

NN

H2N

H2N NH2

NH2H2

catalyst

Figure 3.33. Synthesis of PPI dendrimers via alternating Michael addition and hydrogenation.

155

Majoral et al. developed novel dendrons containing Michael acceptors consisting of

CH2=CH-P=N-P=S-(O-R)2 or CH2=CH-P=N-P=O-(O-R)2 groups at the dendrimer core.

This allowed convergent synthesis of dendrimers via coupling of the dendrons through

Michael addition with primary diamine donors (Figure 3.34).346,347

346 Maraval, V.; Laurent, R.; Merino, S.; Caminade, A. M.; Majoral, J. P. Michael-type addition of amines to the vinyl core of dendrons 2. Application to the synthesis of multidendritic systems. Eur J Org Chem 2000, 21, 3555-68. 347 Maraval, V.; Laurent, R.; Donnadieu, B.; Mauzac, M.; Caminade, A. M.; Majoral, J. P. Rapid synthesis of phosphorus-containing dendrimers with controlled molecular architectures: first example of surface-block, layer-block, and segment-block dendrimers issued from the same dendron. J Am Chem Soc 2000, 122, 2499-511.

156

PPh

PhN P

S

Dendron PPh

PhN P

S

DendronNH

H2Nethylene diamine

PPh

PhN P

S

Dendron

PPh

PhN P

S

DendronNH

HNP

Ph

PhNP

S

Dendron

Figure 3.34. Convergent dendrimer synthesis via dendron core-linking Michael addition

reactions.

157

Peripheral modification of dendrimers was also accomplished via Michael reactions

with pendant Michael donors or acceptors. For instance, mesogenic cyanobiphenyl

acrylates were introduced onto amine terminated poly(propylene imine) dendrimers resulting

in liquid crystalline dendrimer molecules. 348 Michael addition of acryloxylethyl

methacrylate to amine terminated dendrimers resulted in photocrosslinkable dendrimer

methacrylates.349 The Michael addition scheme was the only successful functionalization

methodology as reaction with isocyanatoethyl methacrylate or acetoacetoxy methacrylate

resulted in insoluble, crystalline products and reaction with methacrylic anhydride did not

completely functionalize the terminal amines. The methacrylated dendrimers exhibited

nearly quantitative cure reactions as determined through differential scanning calorimetry

(DSC). In Figure 3.35, dendritic acrylate oligomers were also synthesized through the

Michael addition of trimethylolpropane triacrylate (TMPTA) with ethylene diamine in a 5:1

ratio.350,351 The desired product possessed a TPMTA:EDA ratio of 4:1, however, network

formation occurred under these conditions. The branched oligoacrylates resembled

dendrimers with low viscosities and facile cure conditions using UV-photocuring techniques.

Purification of these dendrimers was achieved primarily through precipitation.

348 Yonetake, K.; Masuko, T.; Morishita, T.; Suzuki, K.; Ueda, M.; Nagahata, R. Poly(propyleneimine) dendrimers peripherally modified with mesogens. Macromolecules 1999, 32, 6578-86. 349 Moszner, N.; Volkel, T.; Liechtenstein, S. Synthesis, characterization and polymerization of dendrimers with methacrylic end groups. Macromol Chem Phys 1996, 197, 621-31. 350 Xu, D. M.; Zhang, K. D.; Zhu, X. L. A novel dendritic acrylate oligomer: synthesis and UV curable properties. J Appl Polym Sci 2004, 92, 1018-22. 351 Xu, D. M.; Zhang, K. D.; Zhu, X. L. Synthesis and characterization of dendrimers from ethylene diamine and trimethylolpropane triacrylate. J Macromol Sci Part A: Pure Appl Chem 2005, 42, 211-9.

158

NH2H2N

O

O

O

O

O

ONN

O

O

O

O

OO

O

O

O

O

OO

O

O

O

O

O O

O

OO

O

OO

+

Figure 3.35. Crosslinkable dendrimer synthesis using Michael addition reactions.

159

3.6.2 Hyperbranched and Highly Branched Polymers

Hyperbranched polymers were initially developed as inexpensive, one-pot substitutes

for dendrimers, but have developed a unique character over the last several years.

Hyperbranched polymers were traditionally approached from asymmetric monomer synthesis

(ABn monomers). Difficult monomer synthesis is a major disadvantage of the ABn method

due to a lack of commercial ABn monomer sources. Recently, An + Bm approaches were

used to synthesize hyperbranched polymers, enabling a much wider range of monomers and

topologies. A further development is the use of oligomeric An or Bm monomers, resulting in

“highly branched polymers”, which allows control of the molecular weight between branch

points, an important parameter that affects degree of entanglement and has performance

implications.352 Michael addition reactions were successfully applied to both the AB2 and

An + Bm strategies for hyperbranched polymer synthesis.

In a conventional AB2 hyperbranching polymerization, Endo et al. conducted

acetoacetylation of hydroxyethyl acrylate through a reaction with diketene. 353 This

produced an AB2 monomer that was capable of producing hyperbranched Michael addition

polymers in the presence of base catalyst (Figure 3.36). Polymerization of this novel

monomer in the presence of DBU resulted in number average molecular weights between

2000 and 12000 g/mol with dispersities between 1.4 and 3.5 and degrees of branching

between 43 and 83%. A high ratio of dendritic to linear units was observed, suggesting

352 Unal, S.; Lin, Q.; Maurey, T. H.; Long, T. E. Tailoring the degree of branching: preparation of poly(ether ester)s via copolymerization of poly(ethylene glycol) oligomers (A2) and 1,3,5-benzenetricarbonyl trichloride (B3). Macromolecules 2005, 38, 3246-54. 353 Kim, Y. B.; Kim, H. K.; Nishida, H.; Endo, T. Synthesis and characterization of hyperbranched poly(β-ketoester) by the Michael addition. Macromol Mater Eng 2004, 289, 923-6.

160

greater reactivity of the mono-Michael adduct towards the acrylate group compared to the

reactivity of the original acetoacetate group.

161

O O

O O

O

O O

O O

O

O

O

O

O

O

O

O

O

O

O

O O

O O

O

O O

O O

O

OO

OO

O

O O

OO

O

O O

OO

O

OO

OO

O

H H

H HH H

H

H H

H H

H

DBU

Figure 3.36. Hyperbranched polymer synthesis via AB2 Michael addition polymerization.

162

Trumbo studied the step growth polymerization of low molar mass diacrylates

(tripropylene glycol diacrylate) with bisacetoacetates354 and bisacetoacetamides.355 These

systems formed branched structures due to the difunctionality of the acetoacetate group.

Gelation of the reaction mixture was avoided with an excess of bisacetoacetate monomer and

through conducting the reaction in solution with a relatively mild base catalyst (DBU).

Weight average molecular weights as high as 437000 g/mol were observed, however broad

dispersities (Mw/Mn~10) were typical, which further suggested branching in this system.

Decreases in molecular weight and dispersity with reaction time were observed during these

polymerizations, suggesting the occurrence of a retro-Michael addition and subsequent

equilibration.

Hyperbranched poly(aspartamide)s were synthesized from bismaleimides and aromatic

triamines using the A2+B3 methodology.356 The reaction stoichiometry was limiting in

bismaleimide, thus controlling the extent of the reaction and favoring secondary amine

terminated products. The hyperbranched polymers exhibited degrees of branching near 0.51

and 0.69, high glass transition temperatures (~210 to 250 oC) as well as equivalent thermal

stability to analogous linear polymers. In Figure 3.37, a tris(4-aminophenyl)phosphine

oxide triamine was used to create polymers with higher thermal stability and also to allow

degree of branching determination through 31P NMR.

354 Trumbo, D. L. Michael addition polymers from 1,4- and 1,3-benzenedimethanol diacetoacetates and tripropylene glycol diacrylate. Polym Bull 1991, 26, 265-70. 355 Trumbo, D. L. Michael addition polymers from bisacetoacetates II. 2,2-dimethyl-1,3-bis(acetoacetyl)-propanediol and N,N'-bis(acetoacetyl)-1,4-piperazine. Polym Bull 1991, 26, 481-5. 356 Liu, Y. L.; Tsai, S. H.; Wu, C. S.; Jeng, R. J. Preparation and characterization of hyperbranched polyaspartimides from bismaleimides and triamines. J Polym Sci Part A: Polym Chem 2004, 42, 5921-8.

163

P

H2N

H2NNH2

O

N N

O

O O

O

P

HN

HNHN

O

N

N

O

O

O

ON N

O

O O

O

N N

O

O O

OP

H2N

NH

NH2

O

Figure 3.37. Hyperbranched poly(aspartamide)s via A2 + B3 polymerization.

164

Feng et al. studied hyperbranched poly(amino ester)s that were synthesized from

piperazine and trimethylolpropane triacrylate in molar ratios ranging from 1:1.08 to 1:2.357

These hyperbranched polymers formed aggregates in acetone/acidic water, which were

proposed to contain a hydrophobic acrylate rich core and a hydrophilic, protonated amine

periphery. The aggregates were crosslinked using UV light via reaction of residual acrylate

groups. The size of the aggregates (DLS, TEM) decreased upon crosslinking and were

smaller for higher molecular weight polymers, suggesting a packing efficiency limitation

with the higher molecular weight, more disperse, polymers. Enhanced aggregation of

similar poly(amino ester)s was achieved through reaction of peripheral amine groups with

long chain acyl halides.358

Wu et al. studied the effect of unequal functional group reactivity in a hyperbranching

A2 + B3 system with a butanediol diacrylate A2 and a trifunctional amine B3 containing both

primary (f = 2) and secondary (f = 1) amines (Figure 3.38).359 For an equimolar A2:B3 ratio,

1H NMR studies indicated that secondary amines were consumed prior to primary amines.

The secondary amine that was formed from reaction of the primary amine and the acrylate

group was not consumed, and thus a predominantly linear product was obtained despite the

functionality of the monomers. The reactivity of the amines was secondary > primary >>

formed secondary. If the A2:B3 ratio was increased, participation of the formed secondary

357 Tang, L.; Fang, Y.; Feng, J. Structure, solution aggregation and UV curing of hyperbranched poly(ester amine)s with terminal acrylate groups. Polym J 2005, 37, 255-61. 358 Tang, L.; Fang, Y.; Tang, X. Influence of alkyl chains of amphiphilic hyperbranched poly(ester amine)s on the phase-transfer performances for acid dye and the aggregation behaviors at the interface. J Polym Sci Part A: Polym Chem 2005, 43, 2921-30. 359 Wu, D.; Liu, Y.; He, C.; Chung, T.; Goh, S. Effects of chemistries of trifunctional amines on mechanisms of Michael addition polymerizations with diacrylates. Macromolecules 2004, 37, 6763-70.

165

amine during the reaction of the primary amine occurred, thus resulting in a branched product.

If the steric hindrance at the secondary amine position was increased, the primary amine was

the most reactive and the reaction proceeded at the formed secondary amine during the

reaction and again the product was branched. Thus, both the level of substitution of the

amine groups and the stoichiometric ratio of the reactants controlled the degree of branching.

Degrees of branching that ranged from 30 to 40% and weight average molecular weights as

high as 23,500 g/mol were obtained.

166

HNN

OO

OO

4

HNN

HN O

OO

O4

OO

OO4

NN NH2 O

OO

O4N

NHN

n

NH2

+

Figure 3.38. Hyperbranched poly(ester amine)s from A2 + B3 polymerization with unequal

reactivity in the B3 monomer functional groups.

167

Wu et al. also studied hyperbranched poly(amino ester)s that were synthesized using

two equivalents of butanediol acrylate and one equivalent of 1-(2-aminoethyl)piperazine.360

Due to the higher reactivity of the secondary cyclic amine, the Michael addition with

butanediol diacrylate occurred preferentially. The primary amino group reacted second,

resulting in the in-situ generation of an AB2 intermediate that undergoes a branching at the

secondary amine formed from the primary amine. The ratio of Rh to Rg of 1.0 as measured

by SAXS and DLS demonstrated the hyperbranched nature of the polymers. The

hyperbranched polymers had number average molecular weights of 29000 to 38000 g/mol

and dispersities of 3.4 to 3.7.

In similar work, Gao et al. synthesized hyperbranched polymers from diethanolamine

and methyl acrylate.361 The reaction proceeded through an initial Michael addition reaction

to form an ester diol AB2 monomer in-situ that self-condensed at elevated temperature (150

ºC) through transesterification in the presence of a zinc acetate catalyst. Number average

molecular weights as high as 268000 g/mol were observed with a polydispersity of 2.4.

Crosslinking occurred when the temperature in the second stage exceeded 160 ºC, whereas

lack of polycondensation occurred if the temperature was less than 120 ºC. The degree of

branching of these polymers was roughly 55%. These polymers degraded rapidly in water

to form self-buffered pH 7 solutions, suggesting them as good candidates for drug delivery.

Hyperbranched poly(amido amine) hydrochloride polyelectrolytes were synthesized

through the Michael addition polymerization of AB2 monomers based on ammonium alkyl

360 Wu, D.; Liu, Y.; Chen, L.; He, C.; Chung, T. S.; Goh, S. H. 2A2 + BB’B” approach to hyperbranched poly(amino ester)s. Macromolecules 2005, 38, 5519-25. 361 Gao, C.; Xu, Y.; Yan, D.; Chen, W. Water-soluble degradable hyperbranched polyesters: novel candidates for drug delivery? Biomacromolecules 2003, 4, 704-12.

168

acrylamides, as shown in Figure 3.39.362 The lack of nucleophilicity of the ammonium

group toward the acrylamide functionality required the use of high temperatures (210 ºC) in

order to drive the polymerization. It was postulated that a small equilibrium concentration

of free amine that exists at these high temperatures undergoes the Michael addition. The

shorter alkylene spacer (n = 2) between the acrylamide group and the ammonium group

resulted in faster reaction, and an intramolecular deprotonation through a six membered

cyclic transition state was proposed. Model reactions suggested that the ammonium group

reacts twice with acrylamide functionalities, resulting in a highly branched product. 15N

NMR was used to characterize the degree of branching in these materials. Signals from

linear units were not observed, corroborating the highly branched nature of the polymer.

This methodology is a more facile route to hyperbranched polymers resembling PAMAM

dendrimers.

362 Hobson, L. J.; Feast, W. J. Poly(amido amine) hyperbranched systems: synthesis, structure and characterization. Polymer 1999, 40, 1279-97.

169

O

HN NH2

H O

HN NH

H

ClCl O

NH

NH

nn

n NH

O

NH3nm210 oC

Figure 3.39. Homopolymerization of an AB2 poly(amido amine) monomer.

170

Kadokawa et al. studied the triphenylphosphine initiated Michael addition

polymerization of 2,2-bis(hydroxymethyl)propyl acrylate to yield phosphonium containing

hyperbranched polymers of 1,200 to 2,700 g/mol, as shown in Figure 3.40.363 This is one

of the few examples of oxygen based nucleophiles involved in a Michael addition

polymerization. Degrees of branching near 50% were obtained. Similar polymers were

produced through initiation using sodium hydride. The poor quality of the oxygen

nucleophile for Michael addition is evident in the reaction temperatures (80 to 100 oC, with

free radical inhibitors).364

363 Kadokawa, J.; Kaneko, Y.; Yamada, S.; Ikuma, K.; Tagaya, H.; Chiba, K. Synthesis of hyperbranched polymers via proton transfer polymerization of acrylate monomer containing two hydroxy groups. Macromol Rapid Commun 2000, 21, 362-8. 364 Kadokawa, J.; Ikuma, K.; Tagaya, H. Polymerization of acrylate monomer containing two hydroxyl groups initiated with sodium hydride for synthesis of hyperbranched polymer. J Macromol Sci Pure Appl Chem 2002, A39, 879-88.

171

O

O OH

HO

O

O O

O

Ph3P

n

n

Figure 3.40. Homopolymerization of an AB2 poly(ester ether) monomer.

172

Highly branched gene transfection agents were synthesized through the reaction of low

molecular weight linear PEI with PEG diacrylate.365 The polymers clearly did not represent

linear topologies due to branching in the PEI as well as reaction at multiple amine sites along

the polymer backbone. The presence of ester groups in the polymers facilitated degradation.

The half-lives of the polymers in PBS at 37 oC were approximately 8 d. The polymers

demonstrated complex formation with plasmid DNA and transfection studies were performed.

Branched gene transfection agents were also synthesized via reaction of trimethylolpropane

triacrylate with primary amines such as N,N-dimethylethylenediamine. 366 Polyplex

formation with plasmid DNA was verified with dynamic light scattering and transfection into

various human and mouse cell lines exhibited transfection efficiencies similar to

poly(ethylene imine). The branched nature of the poly(amino ester)s slowed polymer

degradation and hence controlled the release of the plasmid DNA. The branched

poly(amino ester)s showed little or no cytotoxicity.

3.6.3 Graft Copolymers

Graft copolymers are synthesized through numerous routes including chain or step

growth polymerization of macromonomers and post-polymerization grafting. Ferruti et al.

examined graft copolymer synthesis using poly(amido amine)s.367 PEG chains with weight

365 Park, M. R.; Han, K. O.; Han, I. K.; Cho, M. H.; Nah, J. W.; Choi, Y. J.; Cho, C. S. Degradable polyethylenimine-alt-poly(ethylene glycol) copolymers as novel gene carriers. J Contr Rel 2005, 105, 367-80. 366 Kim, T.; Seo, H. J.; Choi, J. S.; Yoon, J. K.; Baek, J.; Kim, K.; Park, J. S. Synthesis of biodegradable cross-linked poly(β-amino ester) for gene delivery and its modification, inducing enhanced transfection efficiency and stepwise degradation. Bioconjugate Chem 2005, 16, 1140-8. 367 Vansteenkiste, S.; Schacht, E.; Ranucci, E.; Ferruti, P. Synthesis of a new family of poly(amido-amine)s carrying poly(oxyethylene) side chains. Makromol Chem 1992, 193, 937-43.

173

average molecular weight of 750 g/mol were incorporated into poly(amido amine) backbones

using monoamine terminated PEG as a comonomer. As a second route, PEG-NH2 was first

reacted with excess bisacrylamide monomer to obtain a PEG bisacrylamide, which was

polymerized with piperazine. In both cases, vapor pressure osmometry indicated that the

molecular weights obtained were quite low (~3000 g/mol). Ferruti concluded that the

reactivity of the PEG-NH2 in the polymerization was lower than typical small molecule

amines. Ferruti et al. also studied poly(amido amine)s grafted to polyethylene via a

post-polymerization strategy, although Michael addition was not involved in the coupling.368

Jerome et al. utilized γ-acryloxy-ε-caprolactone as a graftable comonomer in

copolymerizations with ε-caprolactone.369 In Figure 3.41, pendant acrylate groups were

introduced into poly(ε-caprolactone), permitting grafting of thiol terminated oligomeric PEG

(Mn = 900 g/mol). The Michael addition reaction of various thiols (mercaptoacetic acid and

triphenylmethane thiol) with PEG-acrylate model compounds proceeded to completion.

However, conversions of only 65% and 70% were obtained with PEG-thiol and

mercaptoacetic acid, respectively, in grafting studies with

poly(γ-acryloxy- ε-caprolactone-co-ε-caprolactone).

368 Martuscelli, E.; Nicolais, L.; Riva, F.; Ferruti, P.; Provenzale, L. Synthesis and characterization of a potentially non-thrombogenic polyethylene-poly(amido amine) graft copolymer. Polymer 1978, 19, 1063-6. 369 Rieger, J.; van Butsele, K.; Lecomte, P.; Detrembleur, C.; Jerome, R.; Jerome, C. Versatile functionalization and grafting of poly(ε-caprolactone) by Michael-type addition. Chem Comm 2005, 2, 274-6.

174

OO

HRO

O

O

OO

n m

OOHS

O

x

OO

HRO

O

O

OO

n m

O

O

S

O x

Figure 3.41. Graft copolymerization via grafting of thiol terminated PEG to pendant acryloxy

side groups on a poly(ε-caprolactone) derivative.

175

Much work was done in the area of “grafting to” syntheses utilizing the Michael

addition, especially in the case of biopolymers such as chitin and chitosan. These materials

typically possess poor solubility, which is improved through grafting techniques.

Modification of chitosan with poly(amido amine) dendrimers was achieved by reacting

chitosan surface amine groups with methyl acrylate followed by alternate reactions with

ethylene diamine and further methyl acrylate.370 The heterogeneity and steric hindrance of

the backbone resulted in imperfect dendrimers. Grafting of living cationic poly(methyl

oxazoline) and poly(isobutyl vinyl ether) onto the pendant amine groups of the grafted

poly(amido amine) dendrimers was achieved successfully. Modification of chitin with small

molecules was also achieved through Michael addition to pendant amine groups. Reaction

with acrylonitrile yielded cyanoethylated chitin371 and reaction with ethyl acrylate afforded

ester-containing chitin372 (Figure 3.42).

370 Tsubokawa, N.; Takayama, T. Surface modification of chitosan powder by grafting of 'dendrimer-like' hyperbranched polymer onto the surface. React Funct Polym 2000, 43, 341-50. 371 Tokura, S.; Nishi, N.; Nishimura, S.; Ikeuchi, Y. Studies on chitin X. Cyanoethylation of chitin. Polym J 1983, 15, 553-6. 372 Aoi, K.; Seki, T.; Okada, M.; Sato, H.; Mizutani, S.; Ohtani, H.; Tsuge, S.; Shiogai, Y. Synthesis of a novel N-selective ester functionalized chitin derivative and water-soluble carboxyethylchitin. Macromol Chem Phys 2000, 201, 1701-8.

176

O OO OHO

NHAc

OH OH

HO

NH2n

O OO OHO

NHAc

OH OH

HO

NH

OO

OH

HO

NH2m

OOEt

ethyl acrylate

phosphate buffered methanol

Figure 3.42. Modification of chitin via Michael addition reaction with ethyl acrylate.

177

3.7 Novel Networks via the Michael Addition Reaction

Network polymers that are synthesized via Michael addition reactions offer applications

in diverse areas such as drug delivery systems, high performance composites, and coatings.

Networks are often synthesized through a combination of Michael addition step growth

chemistry combined with chain growth polymerization using photoinitiated radical or anionic

processes. The Michael addition is suited to the formation of well-defined networks due to

the commercial availability or facile synthesis of narrow molecular weight distribution

functional oligomers. Commercially available reactive oligomers include PEG diacrylate

and numerous oligomeric diamines such as Jeffamine®. Several classes of Michael addition

networks are currently of interest.

3.7.1 Bismaleimide Networks and Composite Materials

Currently, bismaleimide based networks are used in high performance fiber-reinforced

composite materials373 and also in thermoset resins. These materials have applications in

the aerospace industry due to their high temperature strength, mechanical robustness, and low

density.374 In the absence of other components, bismaleimides crosslink through chain

growth type reactions at high temperature to form highly crosslinked, high-Tg networks.

Vitrification in these systems leads to incomplete conversion of maleimide groups.

Brittleness is the primary drawback of these homopolymerized networks. Efforts to reduce

the crosslink density and hence the brittleness of these thermosets have involved Michael

373 Fry, C. G.; Lind, A. C. Curing of bismaleimide polymers: a solid-state 13C-NMR study. New Polym Mater 1990, 2, 235-54. 374 Curliss, D. B.; Cowans, B. A.; Caruthers, J. M. Cure reaction pathways of bismaleimide polymers: a solid-state 15N NMR investigation. Macromolecules 1998, 31, 6776-82.

178

addition chain extension reactions with primary or secondary diamines to consume some of

the maleimide functional groups. 375 The chain extension process results in greater

toughness and improved mechanical properties for composites. The introduction of

diamines such as methylene dianiline (MDA) causes a low temperature Michael addition

polymerization (<180 oC) during initial curing, followed on further heating (180 to 220 oC)

with a crosslinking homopolymerization of the maleimide groups (Figure 3.43).376 , 377

Under certain conditions, secondary amines formed during the initial Michael addition

undergo further Michael addition crosslinking with maleimide groups. Hyperbranched

amine terminated polyamides were also investigated as components of bismaleimide

networks, successfully improving the toughness of these systems.378

375 Wu, C. S.; Liu, Y. L.; Chiu, Y. S. Synthesis and characterization of new organosoluble polyaspartamides containing phosphorus. Polymer 2002, 43, 1773-9. 376 Curliss, D. B.; Cowans, B. A.; Caruthers, J. M. Cure reaction pathways of bismaleimide polymers: a solid-state 15N NMR investigation. Macromolecules 1998, 31, 6776-82. 377 Baek, J. B.; Ferguson, J. B.; Tan, L. S. Room-temperature free-radical-induced polymerization of 1,1'-(methylenedi-1,4-phenylene)bismaleimide via a novel diphenylquinoxaline-containing hyperbranched aromatic polyamide. Macromolecules 2003, 36, 4385-96. 378 Kumar, A. A.; Alagar, M.; Rao, R. M. V. G. K. Synthesis and characterization of siliconized epoxy-1, 3-bis(maleimido)benzene intercrosslinked matrix materials. Polymer 2002, 43, 693-702.

179

R NH2

R' N

R

NH

R'

NO

O

O

OR' N

O

O

R'N

O

O

Michael additionT < 180 oC

CrosslinkingT > 180 oC

+

Figure 3.43. Crosslinking of bismaleimide networks via a combination of Michael addition and

maleimide homopolymerization.

180

Kumar et al. incorporated bismaleimide crosslinking systems into silicon-containing

epoxy resin networks.379 The bismaleimides increased the flexural and tensile modulus, but

decreased fracture toughness of the epoxy networks by introducing a more rigid, higher Tg

component. This network reinforcement was due to the thermal cure and Michael addition

reactions between the bismaleimide and the amines from the epoxy resin and the added

diamine.

Bismaleimide networks are useful as NLO materials as well as composites due to their

high glass transition temperatures and crosslink densities. These features are attractive for

NLO materials for maintenance of the chromophore orientation. Furthermore, the absence

of volatile by-products during cure allows poling during this process. Wu et al. synthesized

a diamine NLO chromophore and incorporation into bismaleimide networks resulted in

nonlinear optical coefficients as high as d33 = 60 pm/V at 1064 nm.380 Upon heating, the

second harmonic generation (SHG) was stable to 120 oC, although the cure process was

continued 250 oC in order to maximize crosslinking. Maintenance of the poling field during

the cooling process maximized the NLO properties.

3.7.2 Carbon Michael Addition Networks Utilizing Acetoacetate Chemistry

Considerable interest in Michael addition networks from acetoacetate and acrylate

precursors has recently emerged. These networks are interesting due to the relatively low

toxicity of the components and their room temperature processing in the absence of UV

379 Kumar, A. A.; Alagar, M.; Rao, R. M. V. G. K. Synthesis and characterization of siliconized epoxy-1, 3-bis(maleimido)benzene intercrosslinked matrix materials. Polymer 2002, 43, 693-702. 380 Wu, W.; Zhang, Z.; Zhang, X. Synthesis of NLO diamine chromophore and its use in the preparation of functional polyimides. Des Mon Polym 2004, 5, 423-34.

181

radiation. Furthermore, functionalization of common polyols with the acetoacetate group is

achieved through transesterification with tert-butylacetoacetate381 or reaction with diketene

precursors382 providing a facile route to crosslinkable precursors from a wide variety of

hydroxyl containing feedstocks.

Room temperature thermosetting coatings is one of the primary applications of Michael

addition networks. The Michael addition mechanism is advantageous as neither UV

radiation nor heat are required, both of which could be deleterious to the substrate and require

additional processing equipment. The base catalyzed carbon Michael addition of

acetoacetylated resins to acrylate acceptors, as depicted in Figure 3.44, is an ideal route to

crosslinked networks due to the difunctionality of the acetoacetate group and the absence of

undesirable toxic amine and malodorous thiol nucleophiles in industrial processes. Acrylic

monomers and oligomers are useful candidates for the formation of coatings and adhesives

with highly reduced volatile organic compounds (VOCs) and improved material performance

properties. Although UV curing is not necessary for network formation, the presence of

photocrosslinkable groups in these systems allows tandem Michael and radical curing

mechanisms.

381 Witzeman, J. S.; Nottingham, W. D. Transacetoacetylation with tert-butyl acetoacetate: synthetic applications. J Org Chem 1991, 56, 1713-8. 382 Clemens, R. J.; Hyatt, J. A. Acetoacetylation with 2,2,6-trimethyl-4H-1,3-dioxin-4-one: A convenient alternative to diketene. J Org Chem 1985, 50, 2431-5.

182

OO

O

O

OR'O

+

OO

RO

O OR'O

OO

RO

OOR'O

O25oCbase catalyst

R

n

OO

O

OORO

OR'O

O

O

O

OR

network

Figure 3.44. Carbon-Michael addition polymerization of acetoacetates with acrylates

catalyzed by bases for network synthesis.

183

Clemens and Rector studied the carbon Michael addition reaction between model

compounds, and concluded that the reaction mechanism involved an equilibrium

deprotonation of the acetoacetate and subsequent rate limiting addition of the enolate to the

acrylate group.383 Thus, the rate of the reaction was unaffected by the acetoacetate

concentration but was directly proportional to the base catalyst concentration. The effect of

various catalysts was investigated and as expected, higher basicity led to faster reaction

kinetics. Typical base catalysts included DBU and TMG as well as hydroxide and

methoxide bases. A striking difference, however, was observed in the degree to which

bisadducts of acrylates with acetoacetates formed as a function of catalyst. Amidine and

guanidine bases resulted in higher formation of bisadducts while monoadducts were favored

by methoxide and hydroxide bases. Weaker bases such as triethylamine were not strong

enough to deprotonate the acetoacetate groups and did not catalyze the Michael addition

reaction effectively.

Clemens and Rector prepared crosslinked coatings consisting of randomly

functionalized acetoacetylated precursors such as methyl methacrylate / acetoacetyloxyethyl

methacrylate random copolymers with low molar mass multiacrylates such as

trimethylolpropane triacrylate.383 The level of functionality of the methacrylate copolymers

strongly influenced cure times, with a doubling of the acetoacetate functionality resulting in a

75% reduction in cure time. Acetoacetylated cellulose was also investigated, and the more

rigid character of the polymer coupled with the lack of a spacer between the backbone and

the acetoacetate groups resulted in slower cure reactions. One disadvantage of the Michael


184

crosslinked coatings was hydrolytic instability that was attributed to hydrolysis of the ester

linkages in the presence of the base catalyst. Heat treatments reduced the hydrolytic

instability of the network.

Marsh described the use of high solids acetoacetate-containing resins for coatings

applications.384 High solids polyester resins containing hydroxyl groups were synthesized

and acetoacetylated to various levels. It was found that increasing levels of acetoacetyl

groups lowered the Tg of the polyester resins significantly to yield solvent-free low viscosity

resins. The crosslinking of the pendant acetoacetyl groups using Michael type reactions

with electron deficient olefins and DBU base catalyst (pH = 12.6) afforded formaldehyde-

and isocyanate-free room temperature curable coatings.

Tung published a review on the performance of coatings made from multifunctional

acrylate resins containing reactive diluents and acid blocked catalysts and compared them to

two-package polyurethanes.385 The use of a formic acid neutralized DBU catalyst yielded

better pot life and humidity resistance of the coatings when compared to the highly basic

DBU catalyst. It was found that incorporation of 10 to 15 mol% of a reactive diluent such

as 2,2,4-trimethyl-1,3-pentane-bis(acetoacetate) resulted in low VOC coatings with desirable

ultimate properties. Various multifunctional acrylate crosslinkers were investigated to

determine the influence of crosslinker functionality on the resulting resin properties. A

mixture of tri- and tetraacrylates produced the best hardness, flexibility, solvent resistance,

humidity resistance, adhesion, and weatherability compared to the triacrylates or

384 Marsh, S. J. Acetoacetate chemistry- crosslinking versatility for high-solids coatings resins. Am Chem Soc, Div Polym Chem: Polym Prepr 2003, 44, 52-3. 385 Tung, C. C. Recent advances in isocyanate free coatings: use of acetoacetylated polymers in Michael crosslinking technology. Surface Coatings, Australia 1999, 36, 10-15.

185

hexaacrylates.

3.7.3 Curing Mechanisms Involving Michael Addition with Photocrosslinking or Sol-Gel

Chemistry

Cure mechanisms using a combination of Michael addition and photoinitiated radical

curing are currently of interest due to higher crosslink densities and functional group

conversions. The use of multifunctional acrylate monomers in the carbon Michael addition

networks is ideal for photocrosslinking. Residual acrylate dangling ends must be limited to

maximize chemical and physical durability. Moszner and Rheinberger synthesized networks

from multiacrylates such as PEG diacrylates, trimethylolpropane triacrylate, and

pentaerythritol tetraacrylate with bisacetoacetates such as PEG bis(acetoacetate) and

hexanediol bis(acetoacetate) using DBN base catalyst.386 Isothermal DSC studies revealed

less than 25% of the double bonds were consumed via Michael addition during cure. The

conversion of acrylate groups increased for longer, more flexible, spacers to approximately

71%. Subsequent photocuring of the Michael addition networks using

camphorquinone/N-(2-cyanoethyl)-N-methylaniline resulted in dramatically improved

hardness and conversion of the acrylate groups. Moy et al. developed photocrosslinked

networks from crosslinkable oligomers that were synthesized using Michael addition with an

excess of multiacrylates relative to acetoacetate precursors.387 The Michael addition of

386 Moszner, N.; Rheinberger, V. Reaction behavior of monomeric β-ketoesters, 4) Polymer network formation by Michael reaction of multifunctional acetoacetates with multifunctional acrylates. Macromol Rapid Commun 1995, 16, 135-8. 387 Moy, T. M.; Hilliard, L.; Powell, D.; Loza, R. Liquid oligomers containing unsaturation. US Patent 5,945,489, 1999.

186

acetoacetoxyethyl methacrylate with multifunctional acrylates is another route to

photocrosslinkable methacrylate oligomers. The ketone-containing oligomers were capable

of self-initiation in UV light due to Norrish type cleavage reactions. Klee et al. conducted

Michael addition using diamines and acryloxylethyl methacrylate to create crosslinkable

branched multimethacrylate oligomers for dental composites with lower shrinkage upon

photocrosslinking. 388 Dammann and coworkers demonstrated the formation of liquid

oligomeric Michael adducts by reacting di-, tri- and tetraacrylates with ethyl acetoacetate in a

specific ratio in the presence of catalytic amounts of epoxide and quaternary ammonium salt.

These compositions were further crosslinked to obtain coatings, laminates, and adhesives.389

Pavlinec and Moszner further studied crosslinked networks from poly(propylene glycol)

bis(acetoacetate) or pentaerythritol tetrakis(acetoacetate) and pentaerythritol tetraacrylate

cured with DBN. 390 In these Michael addition networks, a 2:1 ratio of acrylate to

acetoacetate was studied. The residual acrylate groups in the networks were studied using

FTIR, following the acrylate vinyl absorbance at 810 cm-1. The concentration of residual

unreacted acrylate groups was lowest for networks that were prepared using poly(propylene

glycol) bis(acetoacetate)s due to the molecular mobility and long distance between crosslink

points. Higher conversion of reactive functional groups for longer precursors was also

388 Klee, J. E.; Neidhart, F.; Flammersheim, H. J.; Mulhaupt, R. Monomers for low shrinking composites, 2a. Synthesis of branched methacrylates and their application in dental composites. Macromol Chem Phys 1999, 200, 517-23. 389 Dammann, L. G.; Gould, M. L. Liquid uncrosslinked Michael addition oligomers prepared in the presence of a catalyst having both an epoxy moiety and a quaternary salt. US Patent 6,706,414, 2004. 390 Pavlinec, J.; Moszner, N. Photocured polymer networks based on multifunctional β-ketoesters and acrylates. J Polym Sci Part A: Polym Chem 1997, 10, 165-78.

187

observed in photocrosslinking studies of diacrylate oligomers.391 Ambient temperature

aging and thermal postcure treatments to 200 ºC increased the conversion of acrylate groups

from 88% to nearly 97%. The gel fractions that were obtained for the Michael addition

networks ranged from 87% to 94%. The combination of Michael addition curing with free

radical photocuring was also investigated with the addition of photoinitiators, excess

pentaerythritol tetraacrylate, and PEG dimethacrylate monomers to selected compositions.

The stability of the methacrylate against Michael addition prevented interference between the

two cure mechanisms performed in a stepwise manner, beginning with a dark Michael cure

and ending with the photocure. In the photocured systems, lower viscosity during the

Michael addition stage was attributed to the additional PEG dimethacrylate monomer and

excess acrylate monomer. This was postulated to improve the cure process by improving

molecular mobility and homogeneity.

Michael reactions between multifunctional acrylates and acetoacetates have found

widespread applications in the formation of radiation curable coatings, printing ink

formulations, and adhesives. UV curable ink formulations have gained importance as a

substitute to solvent-based ink systems. Currently available UV curable ink formulations

exhibit rapid curing under commercial line speeds, however, large quantities of photoinitiator

such as benzophenone are required to ensure complete curing throughout the thickness of the

film for printing applications. These photoinitiators are known to be toxic, expensive and

also cause odor and color in the material. In order to overcome this issue, current studies

have involved the use of liquid oligomeric Michael adducts formed from multifunctional

391 Kurdikar, D. L.; Peppas, N. A. A kinetic study of diacrylate photopolymerizations. Polymer 1994, 35, 1004-11.

188

acrylates by reaction with Michael donors such as acetoacetate compounds, which are

amenable to further crosslinking under UV irradiation.392 Through the incorporation of

suitable additives such as acrylic monomers and oligomers, vinyl monomers, vinyl ethers,

and primary and secondary amines, ink formulations were modified to obtain rheological and

adhesion characteristics that were desirable for printing applications on many different kinds

of substrates.

Recently Liu et al. described the formation of renewable and environmentally benign

wood adhesives based on derivatized soy protein using the Michael addition crosslinking

approach.393 Soy proteins used as renewable wood adhesives suffer from low shear strength

and moisture resistance. In order to improve the properties of the adhesive, the authors first

maleated the soy protein isolates (SPI) using maleic anhydride, which was then reacted with

poly(ethylene imine) via Michael addition. Wood composites that were bonded with

adhesive exhibited shear strength of 7.0 MPa as compared to 2.0 MPa of those bonded using

SPI. In addition the joints also gained water resistance.

In addition to the application of the Michael addition in the formation of crosslinked

coatings, the formation of reactive intermediates through Michael additions which are

subsequently crosslinked using other mechanisms yields useful coatings and adhesives.

This strategy has often involved sol-gel chemistry of the Michael adducts to form networks.

For example, Wilkes et al. have reported the formation of bis- and tris(maleimide)

392 Narayansarathy, S.; Gould, M.; Zaranec, A.; Hahn, L. Radiation-curable inks and coatings from novel multifunctional acrylate oligomers. Technical Conference Proceedings-UV & EB Technology Expo & Conference, Charlotte NC, May 2004, 447-59. 393 Liu, Y.; Li, K. New wood adhesive based on modified soy protein. Abstracts of Papers, 229th ACS National Meeting, Cell-143, March 2005.

189

functionalized trialkoxysilanes by Michael addition reaction between 3-aminopropyl

triethoxysilanes and corresponding maleimides. 394 The functionalized silanes were

crosslinked via sol-gel methods and used as protective coatings on polycarbonate substrates

exhibiting enhanced abrasion resistance. Tilley et al. recently described the use of the

Michael addition reaction for the preparation of acrylate-functionalized silane coupling

agents to introduce acrylate functionality to colloidal silica particles.395 Such acrylate

functionalized silica particles were used as toughness enhancers for UV-curable acrylic

coatings. Incorporation of these functionalized silica particles into a wide variety of organic

matrices such as polyesters, epoxies, and polyurethanes was demonstrated. Such inorganic

oxide modified coatings exhibited much greater micro-hardness and abrasion resistance

compared to commercially prepared coatings. In a recent patent disclosure, Kobayashi et al.

reported the synthesis of an acryloxy-functional silicone composition curable by high-energy

radiation. 396 The silicones consisted of a mixture of multifunctional acrylates,

amino-functional alkoxysilanes, organofunctional alkoxysilanes, and colloidal silica. The

resultant coatings exhibited excellent storage stability, transparency, adhesiveness, water

repellency, and abrasion resistance. Zhu et al. also demonstrated the formation of a

trimethoxysilane coupling agents containing O-butyrylchitosan via Michael addition of

3-acryloxypropyltrimethoxysilane with the amino groups of the butyrylchitosan. 397

394 Tamami, B.; Betrabet, C.; Wilkes, G. L. Synthesis and application of abrasion resistant coating materials based on functionalized bis and tris maleimides. Polym Bull 1993, 30, 293-9. 395 Misra, M.; Tilley, G. A. Hybrid inorganic-organic UV-curable abrasion resistant coatings. Surf Coatings Int 1998, 81, 594-5. 396 Nakashima, H.; Wakita, M.; Kobayashi, H. Acryloxy-functional silicone composition curable by high-energy radiation. World Patent Appl. 2004078863, 2004. 397 Zhu, A.; Wu, H.; Shen, J. Preparation and characterization of a novel Si-containing crosslinkable O-butyrylchitosan. Coll Polym Sci 2004, 282, 1222-7.

190

Crosslinking of the modified silanes derivatives resulted in colorless, flexible elastomeric

coatings at 20 mol% incorporation of the modified silane. The resulting hydrogel films

possessed good antithrombogenic properties as determined by blood-clotting and platelet

adhesion.

3.7.4 Hydrogel Networks for Biomedical Applications

Michael addition networks find application in areas beyond composites and coatings.

Recently, numerous biomedical applications were investigated. Hubbell et al. studied

in-vivo gelling networks based on multifunctional thiols and multiacrylates as injectable

tissue reinforcement.398 Currently two mechanical ranges of in-vivo biomaterials exist:

low modulus gels which are used for drug delivery and high modulus bone cements. An

intermediate strength material (0.5-50 MPa) is desirable for tissue reinforcement of

invertebral disc annuli. Michael addition networks based on thiol and acrylate precursors

are ideal due to the ability to control gelation with the addition of a basic catalyst, the absence

of free thiols in the bloodstream, and the faster rate of the thiol-acrylate Michael addition in

comparison to potential Michael reactions with amines in the bloodstream. Metters and

Hubbell also recently demonstrated the biodegradability of these networks via slow

hydrolysis of ester bonds adjacent to sulfide linkages, which leads to degradation on the order

of days to weeks.399 In a separate work, Hubbell et al. showed that the length of the alkyl

spacer between the ester and the sulfide controlled the hydrolysis rate of these poly(ester

398 Vernon, B.; Tirelli, N.; Bachi, T.; Haldimann, D.; Hubbell, J. Water-borne, in situ crosslinked biomaterials from phase-segregated precursors. J Biomed Mater Res 2003, 64A, 447-56. 399 Metters, A.; Hubbell, J. Network formation and degradation behavior of hydrogels formed by Michael-type addition reactions. Biomacromolecules 2005, 6, 290-301.

191

sulfide)s, with higher degradation rates occurring for shorter alkyl spacers. 400 Both

dispersion type and reverse emulsion type polymers were synthesized via mixing network

components with basic PBS. Reverse emulsion type networks exhibited a slower change in

shear storage modulus with time near the gel point and higher ultimate compressive strengths

(6.7 MPa vs. 1.8 MPa) due to greater continuity of the organic phase. Dispersion networks

exhibited rapid increases in shear storage modulus near the gel point, due to the percolation

of dispersed crosslinking particles. Both materials exhibited maximum deformations near

37%. Modulus increased with increased amounts of tetraacrylate precursors versus

diacrylate precursors.

Rizzi and Hubbell developed protein containing hydrogel networks for tissue repair

applications.401 Cysteine-functionalized recombinant proteins containing sequences for

integrin receptor ligation were synthesized and crosslinked with PEG bis(vinyl sulfone)

(Figure 3.45). Integrin receptors are cellular receptors which play important roles in tissue

development processes. These networks were stable to aqueous solution and did not exhibit

hydrolytic degradation. Thus, protease cleavable units were introduced into the proteins to

enable biodegradability. Glutamic acid units were placed strategically near cysteine

residues to inhibit disulfide bond formation prior to crosslinking, while glycine residues were

used to prevent hindrance of the Michael addition.

400 Schoenmakers, R. G.; van de Wetering, P.; Elbert, D. L.; Hubbell, J. A. The effect of the linker on the hydrolysis rate of drug-linked ester bonds. J Contr Rel 2004, 95, 291-300. 401 Rizzi, S. C.; Hubbell, J. A. Recombinant protein-co-PEG networks as cell-adhesive and proteolytically degradable hydrogel matrixes. Part I: Development and physicochemical characteristics. Biomacromolecules 2005, 6, 1226-38.

192

NH Fibrinogen fragment

R

O

R1 R2

S

NH

S

O

R3 Collagen fragmentR4 N

H

S

O

R

n

S

O

O

OO

S

O

On

NH Fibrinogen fragment

R

O

R1 R2

S

NH

S

O

R3 Collagen fragmentR4 N

H

S

O

R

n

S OOSO O SO O

Figure 3.45. Network formation of PEG bis(vinyl sulfone) and protein dithiols.

193

Previous work on cysteine containing peptides revealed that positively charged arginine

groups adjacent to cysteine lower the pKa of the cysteine group, accelerating Michael

reaction by a factor of 2 and decreasing gel time by a factor of 2.5.402 Numerous charged

residues were also used to enhance solubility of the proteins. The crosslinking kinetics were

studied using rheological measurements, which showed increasing storage modulus with time

during the crosslinking reaction. The gel time decreased with increasing pH, due to the fact

that the thiolate ion is the active species in the Michael addition reaction with vinyl sulfone

groups. A maxima in G’ and minimum in gel time was found for a ratio of thiol to vinyl

sulfone (SH:VS) slightly greater than unity and differed with protein precursor. This

non-stoichiometric maximum was likely due to disulfide bond formation during reaction.

Higher storage modulus and lower swelling were generally observed with an increased molar

ratio of thiol to vinyl sulfone (Figure 3.46). A potential explanation for this phenomenon

was decreased accessibility of reactive sites for crosslinking at lower SH:VS ratios. In

similar work featuring non-degrading peptides with two cysteine residues, higher elastic

modulus and lower swelling were observed for PEG bis(vinyl sulfone)s of higher

functionality (3 to 8 arms) due to increased crosslink density.402 Network elastic moduli in

these systems reached a maximum at pH 8, likely because of slower kinetics at pH < 8 and

greater disulfide bond formation at pH > 8. Furthermore, precursor concentration strongly

influenced mechanical properties due to the propensity for cyclization reactions in dilute

conditions.

402 Lutolf, M. P.; Hubbell, J. A. Synthesis and physicochemical characterization of end-linked poly(ethylene glycol)-co-peptide hydrogels formed by Michael-type addition. Biomacromolecules 2003, 4, 713-22.

194

Figure 3.46. a) Effect of pH on gel time for PEG bis(vinyl sulfone). Gel time decreases at

higher pH due to the greater thiolate anion concentration.

b) Effect of thiol to vinyl sulfone ratio (SH:VS) on the storage modulus of PEG-protein

networks. The G’ maxima occurs at ratios slightly greater than unity suggesting disulfide

formation.

Reproduced from “Recombinant protein-co-PEG networks as cell-adhesive and

proteolytically degradable hydrogel matrixes. Part I: Development and physicochemical

characteristics,” Rizzi and Hubbell, Copyright 2005 with permission from the American

Chemical Society.403

403 Rizzi, S. C.; Hubbell, J. A. Recombinant protein-co-PEG networks as cell-adhesive and proteolytically degradable hydrogel matrixes. Part I: Development and physicochemical characteristics. Biomacromolecules 2005, 6, 1226-38.

a)

b)

195

Michael addition networks were also developed for protein drug delivery applications.

Protein drugs often suffer from rapid clearance from the bloodstream due to removal by the

liver or kidneys. The use of drug delivery devices allows steady and long lasting delivery of

protein drugs. Many current drug delivery materials such as poly(lactide)s can potentially

denature the protein drug due to changes in pH associated with degradation byproducts.

Another issue with current drug delivery materials is incorporating the protein into the

material. Hubbell et al. studied Michael addition networks based on PEG multiacrylate and

PEG dithiol that overcame many of these problems via incorporating bovine serum albumin

protein during synthesis in aqueous media at physiological pH without denaturing the protein

(Figure 3.47).404 The crosslinking of these Michael addition networks required no basic

catalyst or UV light that could potentially harm the protein as in photocuring of acrylate

networks. Furthermore, the ester bonds in the PEG networks were degradable, allowing

release of the protein as the network swells. The thiol-acrylate Michael addition reaction

proceeded without significant side reactions with protein based amine nucleophiles,

preserving the chemistry of the protein drugs. Furthermore, protein based free thiols are

uncommon in extracellular proteins, lending greater selectivity to the approach. In cases

where free thiols do exist, they are often confined to sterically hindered locations in the

tertiary structure of the protein. Hubbell et al. introduced the protein as well-defined ~100

μm solid particles which were embedded into the Michael addition network during curing.404

The release rate of the networks was tuned via the functionality of the PEG multiacrylate.

PEG triacrylate networks resulted in rapid release of the protein. PEG tetraacrylate

404 Elbert, D. L.; Pratt, A. B.; Lutolf, M. P.; Halstenberg, S.; Hubbell, J. A. Protein delivery from materials formed by self-selective conjugate addition reactions. J Contr Rel 2001, 76, 11-25.

196

networks released protein over the course of 4 d at a linear rate of 20% per day. PEG

octaacrylate networks exhibited a slower release with a release rate of 10 to 15% per day.

Hydrolytic degradation was observed in the swelling kinetics of these networks. A decrease

in gel time with increasing solution pH (up to pH 8.2) indicated that the thiolate anion is the

active species in the Michael addition with the acrylate.

197

Figure 3.47. Release of albumin from PEG networks based on PEG tetraacrylate (black

squares) and PEG octaacrylate (white triangles). The lower functionality of the PEG

tetraacrylate leads to lower crosslink density and more rapid release. Reprinted from J.

Control Rel, 76, Hubbell et al. “Protein delivery from materials formed by self-selective

conjugate addition reactions,” 11-25, Copyright 2001, with permission from Elsevier.405

405 Elbert, D. L.; Pratt, A. B.; Lutolf, M. P.; Halstenberg, S.; Hubbell, J. A. Protein delivery from materials formed by self-selective conjugate addition reactions. J Contr Rel 2001, 76, 11-25.

198

Hubbell et al. also studied protein drug delivery using Michael addition hydrogel

networks from eight-arm PEG octaacrylate with dithiothreitol (Figure 3.48).406 The protein

drug human growth hormone (hGH), which suffers from rapid clearance was incorporated

into these hydrogels without covalent attachment. Currently, daily administrations of this

drug are required for treatment of the hormone deficiency as well as Turner’s syndrome and

renal failure. The crosslink density of the networks is controlled with the use of varying

molecular weights of PEG octaacrylate, thereby influencing the drug diffusion. As shown

in Figure 3.49, the drug release rate was tuned to occur over periods from hours to months by

changing the crosslink density of the networks. The ester sulfide linkages produced in the

network degraded at a significantly faster rate than in free radically crosslinked acrylic

networks, presumably due to neighboring group effects from the thioether group. Thus, the

diffusion coefficient in these networks increases with time. The degradation rate of these

networks varied from weeks to months and was directly related to the crosslink density.

406 an de Wetering, P.; Metters, A. T.; Schoenmakers, R. G.; Hubbell, J. A. Poly(ethylene glycol) hydrogels formed by conjugate addition with controllable swelling, degradation, and release of pharmaceutically active proteins. J Contr Rel 2005, 102, 619-27.

199

OO

O

n8

HSSH

OH

OH

proteinprotein containing network

Figure 3.48. Protein-containing PEG networks via Michael addition crosslinking of PEG

octaacrylate with dithiothreitol. Human growth factor protein (hGH) was incorporated by

mixing.

200

Figure 3.49. a) Swelling of PEG octaacrylate, dithiothreitol networks via initial solvent

uptake followed by ester hydrolysis leading to degradation. b) Release kinetics of hGH

protein from networks as a function of PEG octaacrylate molecular weight (squares 10000

g/mol, circles 10000 g/mol mixed with 2000 g/mol (50:50), triangles 2000 g/mol). Reprinted

from J Control Rel, 102, van de Wetering et al. “The effect of the linker on the hydrolysis rate

of drug-linked ester bonds,” 619-27, Copyright 2005, with permission from Elsevier.407

407 Schoenmakers, R. G.; van de Wetering, P.; Elbert, D. L.; Hubbell, J. A. The effect of the linker on the hydrolysis rate of drug-linked ester bonds. J Contr Rel 2004, 95, 291-300.

a)

b)

201

Hubbell et al. also studied synthetic cell encapsulation networks.408 These networks

were synthesized from physically gelled four-arm Pluronics® (poly(ethylene

oxide-b-propylene oxide-b-ethylene oxide)) functionalized with acrylate groups and thiols.

These hydrogels have potential applications in cell encapsulation. The propensity of the

thiol groups to undergo disulfide bond formation prompted the use of the thioacetic ester

protecting group which was deprotected during crosslinking. The reversible physical

gelation process for Pluronics occurred in aqueous solution when a cold, slightly acidic

medium (5 ºC, pH = 6.8) was increased both in temperature and pH (37 ºC, pH = 7.4). Once

the physical gel formed, the covalent crosslinking via the Michael addition reaction produced

gels, which were biodegradable due to the presence of ester groups. Degradation in PBS at

physiological conditions occurred over periods of 1 to 2 weeks.

In order to mimic the extracellular matrix and guide the growth of cells, synthetic

matrices should be biocompatible, resistant to non-specific adsorption of proteins, degradable

via cell- secreted matrix metalloproteinases (MMPs), and further promote cell-adhesion.

Extending on an earlier study, Hubbell et al. synthesized hydrogels comprising multiarm

vinyl sulfone-terminated PEG, a monocysteine containing adhesion protein, and a

bis(cysteine) metalloprotein substrate protein. The adhesion peptide was introduced to

provide adhesion sites on the surface of the hydrogel matrix. The unreacted vinyl sulfone

groups were reacted with the bis(cysteine) terminated MMP substrate peptide. Figure 3.50

depicts the stepwise formation of the hydrogel containing the adhesion proteins and the MMP

408 Cellesia, F.; Tirellia, N.; Hubbell, J. A. Towards a fully-synthetic substitute of alginate: development of a new process using thermal gelation and chemical cross-linking. Biomaterials 2004, 25, 5115-24.

202

substrate proteins as well as the attack on the substrate protein by a metalloproteinase.409

Analysis of the activity of an MMP to various substrates in the 3D hydrogel indicated that the

invasion of the cells was dependent on the enzymatic sensitivity of the substrate peptide and

the rate of this process was dependent on the adhesion peptide concentration. Also the

invasion of the cells decreased with an increase in crosslink density at lower PEG molecular

weights. In order to demonstrate the capability of these hydrogels to promote tissue growth

a bone protein containing hydrogel was placed in a rat cranial defect. Bone regeneration

was observed after 4 weeks of hydrogel implantation and depended on the MMP sensitivity

of the networks. 409,410 Enhanced bone regeneration was observed due to the additional

affinity sites for the bone protein in the matrix.411 Similarly, the covalent incorporation of a

vascular endothelial growth factor in the hydrogel matrix alongside adhesion peptides and

MMP substrate peptides aided the regeneration of human endothelial cells and formation of

new vascularized tissue in place of the biomaterial.412

409 Lutolf, M. P.; Lauer-Fields, J. L.; Schmoekel, H. G.; Metters, A.; Weber, F. E.; Fields, G. B.; Hubbell, J. A. Synthetic matrix metalloproteinase-sensitive hydrogels for the conduction of tissue regeneration: Engineering cell-invasion characteristics. Proc Natl Acad Sci USA 2003, 100, 5413-8. 410 Lutolf, M. P.; Raeber, G. P.; Zisch, A. H.; Tirelli, N.; Hubbell, J. A. Cell-responsive synthetic hydrogels. Adv Mater 2003, 15, 888-92. 411 Pratt, A. B.; Weber, F. E.; Schmoekel, H. G.; Müller, R.; Hubbell, J. A. Synthetic extracellular matrices for in situ tissue regeneration. Biotechnol Bioeng 2004, 86, 27-36. 412 Zisch, A. H.; Lutolf, M. P.; Ehrbar, M.; Raeber, G. P.; Rizzi, S. C.; Davies, N.; Schmökel, H.; Bezuidenhout, D.; Djonov, V.; Zilla, P.; Hubbell, J. A. Cell-demanded release of VEGF from synthetic, biointeractive cell growth matrices for vascularized tissue growth. FASEB 2003, 17, 2260-2.

203

Figure 3.50. Illustration of the stepwise synthesis of a PEG-based hydrogel by reacting

multiarm vinyl sulfone-terminated PEG with small amounts of a monocysteine-containing

adhesion peptide (1) followed by reaction of excess bis(cysteine) containing MMP substrate

peptide (2). Attack of a cell-secreted MMP is also shown (3). Structures of the multiarm

vinyl sulfone-terminated PEG (cross lines); monocysteine-containing adhesion peptide (green

wedge shaped arrows), and bis(cysteine) containing MMP substrate peptide (orange divided

squares) are shown in the legend. Reprinted from Proc Natl Acad Sci, 100, Lutolf et al.,

“Synthetic matrix metalloproteinase-sensitive hydrogels for the conduction of tissue

regeneration: Engineering cell-invasion characteristics.” 5413-8, Copyright 2003, with

permission from the National Academy of Sciences, U.S.A.413

413 Lutolf, M. P.; Lauer-Fields, J. L.; Schmoekel, H. G.; Metters, A.; Weber, F. E.; Fields, G. B.; Hubbell, J. A. Synthetic matrix metalloproteinase-sensitive hydrogels for the conduction of tissue regeneration: Engineering cell-invasion characteristics. Proc Natl Acad Sci USA 2003, 100, 5413-8.

204

Ferruti et al. studied tissue scaffolds consisting of crosslinked poly(amido amine)

hydrogels based on 2,2-bisacrylamidoacetic acid, which was crosslinked using primary

diamines.414 The networks degraded completely within 10 d in Dulbecco’s medium at

physiological conditions, and cytotoxicity tests using direct contact with fibroblast cell lines

demonstrated the non-cytotoxic nature of both networks as well as the degradation products.

Bovine serum albumin was also incorporated into selected networks, through mixing with the

network precursors prior to crosslinking. Ferruti et al. developed hydrogels containing

agmatine, a guanidine functionalized amine precursor that resembles the RGD (arginine

glycine aspartic acid) tripeptide, an agent for promoting cell adhesion.415 The mechanical

performance of these tissue scaffolds improved and degradation decreased through the use of

a multi-amine functionalized crosslinker molecule, which was also synthesized through

poly(amido amine) chemistry.

Goethals et al. reacted living cationic, acryloyloxybutyl triflate initiated

poly(tetramethylene oxide) (PTMO) with Astramol™ dendrimers to produce acrylate

functionalized dendrimers (Figure 3.51).416 The presence of both amine and acrylate groups

on the dendrimer molecules resulted in rapid gel formation with gel fractions of 88 to 99%.

The pot life varied from 25 to 125 min with the molecular weight of the PTMO changing

from 1000 to 4000 g/mol. Higher degrees of swelling and higher tensile elongations were

observed for higher molecular weight PTMO precursors. The pot life was also affected by

414 Ferruti, P.; Bianchi, S.; Ranucci, E.; Chiellini, F.; Caruso, V. Novel poly(amido-amine)-based hydrogels as scaffolds for tissue engineering. Macromol Biosci 2005, 5, 613-22. 415 Ferruti, P.; Bianchi, S.; Ranucci, E. Novel agmatine-containing poly(amidoamine) hydrogels as scaffolds for tissue engineering. Biomacromolecules 2005, 6, 2229-35. 416 Tanghe, L. M.; Goethals, E. J.; du Prez, F. Segmented polymer networks containing amino-dendrimers. Polym Int 2003, 52, 191-7.

205

the temperature of the reaction from 45 min at 25 ºC to 4 min at 65 ºC. The gel fraction

increased with the incorporation of four PTMO arms as opposed to two arms.

206

H2NNH2

NH2

NH2

NH2

NH2NH2

H2N

NH2H2NH2N

H2N

H2N

H2NNH2H2N

OO

On

H2NNH2

HN

NH2

NH2

HNNH2

H2N

NH2H2NH2N

NH

H2N

NHNH2H2N

O

On

O

On

O

On

O

On

Figure 3.51. Self-condensing dendrimer synthesized from PPI and acrylate initiated living

PTMO.

207

3.8 Bioconjugates via the Michael Addition Reaction

Strong interest in bioconjugates has developed in recent years. Bioconjugates consist

of synthetic polymers covalently bound to biopolymers (proteins, polysaccharides,

polynucleotides, antibodies) or bioactive species (pharmaceuticals). These materials

possess special properties that make them useful in biomedical applications and fundamental

studies. Coupling synthetic polymers to biomaterials is useful for numerous reasons.

Polymer-protein bioconjugates may possess “stealth” properties, resisting clearance from the

bloodstream in terms of excretion from the liver or kidneys, thus increasing circulatory

lifetimes of protein drugs. Furthermore, recognition properties may be imparted to synthetic

polymers through the incorporation of receptor proteins. Recognition properties are

important in artificial organs and implants as well as in biosensors. Polymer-protein and

polymer-drug conjugates were used to improve solubility and circulation time within the

body. In some cases, biomolecule linking using Michael addition chemistry was studied.

Thus, Roy et al. used Michael addition to create sugar-protein conjugates from

sialyloligosaccharides.417

3.8.1 Polymer-Protein and Polymer-Drug Conjugates

Poly(ethylene glycol) (PEG) is the most common synthetic polymer for coupling with

proteins. PEG is a non-biodegradable polymer ideal for coupling to proteins due to its

biocompatibility and nonabsorbent properties with respect to proteins. Currently, numerous

417 Roy, R.; Laferriere, C. A. Michael addition as the key step in the syntheses of sialyloligosaccharide-protein conjugates from N-acryloylated glycopyranosylamines. J Chem Soc Chem Commun 1990, 23, 1709-11.

208

functional PEGs are commercially available for applications in protein pegylation. 418

Michael addition of protein-bound thiol groups to maleimide functionalized PEG is one of

the most common methods of polymer-protein conjugate synthesis. A second route is

through Michael addition of thiol groups to vinyl sulfone functionalized PEG, resulting in

greater hydrolytic stability. PEG containing two maleimide functional groups was used for

mimicking the heavy chain end of antibodies and is also useful for binding two proteins in

close proximity.418 The coupling of thiol groups on cysteine residues with polymeric

Michael acceptors benefits from several advantages. The Michael addition chemistry occurs

readily at physiological conditions and is selective to thiol-containing proteins over amine

nucleophiles. The reaction also produces no potentially toxic byproducts.419 Hubbell et al.

studied the reactivity of protein-bound cysteine residues as a function of charge

environment.420 Positively charged residues placed adjacent to the cysteine resulted in a

lower pKa of the cysteine group and increased Michael addition to PEG diacrylates.

Negatively charged residues produced the opposite effect. The specific order of the residues

adjacent to the cysteine groups had no apparent effect on reaction kinetics. Vinyl sulfone

functionalized PEG molecules reacted selectively with cysteine residues over lysine residues

at pH 8 and possessed greater hydrolytic stability. Harris et al. coupled reduced

418 Harris, J. M.; Kozlowski, A. Poly(ethylene glycol) derivatives with proximal reactive groups. US Patent 6,664,331, 2003. 419 Heggli, M.; Tirelli, N.; Zisch, A.; Hubbell, J. A. Michael-type addition as a tool for surface functionalization. Bioconjug Chem 2003, 14, 967-73. 420 Lutolf, M. P.; Tirelli, N.; Cerritelli, S.; Cavalli, L.; Hubbell, J. A. Systematic modulation of Michael-type reactivity of thiols through the use of charged amino acids. Bioconjug Chem 2001, 12, 1051-6.

209

ribonuclease with PEG vinyl sulfone.421 Reaction with lysine residues required a higher pH

of 9.3 but was still dramatically slower than the reaction with cysteine at comparable pH.

Lysine residues of proteins also serve as functional group handles for the Michael

reaction of acrylamides. This strategy benefits from the lack of dimerization of lysine

residues in comparison to cysteine residues. A large number of protein-modifying PEG

reagents are directed toward reaction with the amine groups contained in lysine residues.

Such reagents include activated acylating agents such as N-hydroxysuccinimidyl ester-PEG

(NHS-PEG). However, attachment to lysine residues is disadvantageous when the lysine

residues are critical to protein binding or enzymatic active sites. Examples of proteins that

show diminished activity upon pegylation using lysine targeting modified PEGs are

asparaginase, α-galactosidase, and CD4.422 The reaction with lysine groups is also less

controlled and often results in multiple PEG attachments due to the presence of numerous

lysine residues. The use of cysteine via Michael addition to PEG reagents is advantageous

in these cases and further benefits from the lack of synthetic byproducts. Thus, Kogan

synthesized a maleimide terminated PEG capable of reaction with free cysteine residues in

proteins.422

Hubbell et al. have performed a great deal of work in the area of polymer-protein

conjugates, often favoring the method of cysteine Michael addition.423 PEG bisacrylamide

and PEG diacrylate were studied as PEG substrates for coupling with proteins via the

421 Morpurgo, M.; Veronese, F. M.; Kachensky, D.; Harris, J. M. Preparation and characterization of poly(ethylene glycol) vinyl sulfone. Bioconjug Chem 1996, 7, 363-8. 422 Kogan, T. P. The synthesis of substituted methoxy-poly(ethyleneglycol) derivatives suitable for selective protein modification. Syn Comm 1992, 22, 2417-24. 423 Elbert, D. L.; Hubbell, J. A. Conjugate addition reactions combined with free-radical cross-linking for the design of materials for tissue engineering. Biomacromolecules 2001, 2, 430-41.

210

Michael addition. Residual acrylamide or acrylate groups permitted free radical

crosslinking of the resulting pegylated proteins to create hydrogels with embedded proteins

that serve as tissue scaffolds. The reaction of the acrylamide groups with cysteines was

more than an order of magnitude slower than the corresponding acrylate reaction, but the

acrylamide group possesses superior hydrolytic stability. The more hydrolytically stable

and more Michael reactive vinyl sulfone linkage could not be used due to its inability to

polymerize free radically. The tissue scaffold environment is critical to inducing particular

phenotypes to embedded cells. PEG is well known to possess low adhesion to proteins,

which allows the study of specific cell-adhesion agents such as RGD protein. Thus, Hubbell

et al. introduced RGD protein to PEG bisacrylamide and formed networks (Figure 3.52).424

These networks were treated with cells that spread on the surfaces of the network, clearly

well-adhered. Furthermore, the mechanical properties of the crosslinked tissue scaffolds

were sufficient to produce durable materials.

424 Elbert, D. L.; Hubbell, J. A. Conjugate addition reactions combined with free-radical cross-linking for the design of materials for tissue engineering. Biomacromolecules 2001, 2, 430-41.

211

O

NH

O NH

O

n

H2NO

peptide

HS

O

NH

O NH

O

n NH2

O

peptideSpH 8

H2O

Figure 3.52. Protein incorporation via Michael addition of thiol residues to PEG-acrylamide.

212

Polymer-drug conjugates are of special interest in anticancer therapy where numerous

drugs have improved performance in comparison with the parent drug.425 Conjugates of

interest include poly(N-(2-hydroxypropyl)methacylamide) doxorubicin, poly(glutamic

acid)-paclitaxel and PEG-camptothecin. Several reasons exist for the improved

performance of these conjugates including improved solubility, lower toxicity, and longer

retention in the bloodstream. Furthermore, some conjugates benefit from the enhanced

vascular permeability and retention (EPR) effect, in which drugs are preferentially absorbed

into tumor tissue and not released (Figure 3.53). In fact, one reason for the lower toxicity of

the polymer-drug conjugates is the absence of nonspecific uptake into nontargeted tissues and

organs. Generally, polymer-drug conjugates must contain a hydrolysable or

enzyme-cleavable linker to allow cellular uptake of the drug molecules at the tumor site. In

some cases, linkers are introduced that cleave via lysosomic cysteine proteases. Generally,

polymers used in these composites must either biodegrade or possess low enough molecular

weight (< 30000 g/mol) to allow removal through the kidneys.

425 Duncan, R.; Gac-Breton, S.; Keane, R.; Musila, R.; Sat, Y. N.; Satchi, R.; Searle, F. Polymer–drug conjugates, PDEPT and PELT: basic principles for design and transfer from the laboratory to clinic. J Contr Rel 2001, 74, 135-46.

213

Figure 3.53. Drug delivery via polymer-drug conjugates. Enhanced permeability and

retention (EPR) mechanism of drug delivery relies on preferential permeation of the

conjugate followed by drug release, without reverse permeation. Reprinted from J Control

Rel, 74, Duncan et al., “Polymer–drug conjugates, PDEPT and PELT: basic principles for

design and transfer from the laboratory to clinic,” 135-46, Copyright 2001, with permission

from Elsevier.426

426 Duncan, R.; Gac-Breton, S.; Keane, R.; Musila, R.; Sat, Y. N.; Satchi, R.; Searle, F. Polymer–drug conjugates, PDEPT and PELT: basic principles for design and transfer from the laboratory to clinic. J Contr Rel 2001, 74, 135-46.

214

Goodson and Katre accomplished pegylation of recombinant interleukin-2 protein using

PEG-maleimide.427 Interleukin-2 is a glycosylated protein that serves important functions in

the immune system and is useful as an anticancer drug. The recombinant interleukin-2 was

modified to include a cysteine site for Michael addition at the glycosidic linkage of the

original protein, thereby preventing inhibition of the protein. The conjugation of

recombinant interleukin-2 to PEG-maleimide resulted in an increase in hydrodynamic size

and solubility, increasing systemic exposure four fold. An increase in hydrodynamic size

results in less glomerular kidney filtration compared to the unmodified protein. Katre et al.

showed a systematic decrease in clearance with increasing effective molecular weight up to

70000 g/mol above which the rate of clearance was almost constant, possibly due to a

different mechanism of clearance.428 In previous work, modification of interleukin-2 via

amine groups on lysine residues resulted in reduced bioactivity of the protein.429

Jespers et al. studied recombinant staphlokinase pegylated at artificially introduced

cysteine sites using PEG-maleimide.430 Staphlokinase is an enzyme that is used to treat

acute myocardial infarction, through thrombolysis of blood clots within blood vessels.

Numerous sites on the enzyme were targeted for introduction of the cysteine residue. The

427 Goodson, R. J.; Katre, N. V. Site-directed pegylation of recombinant interleukin-2 at its glycosylation site. Bio/technology 1990, 8, 343-6. 428 Knauf, M. J.; Bell, D. P.; Hirtzer, P.; Luo, Z. P.; Young, J. D.; Katre, N. V. Relationship of effective molecular size to systemic clearance in rats of recombinant interleukin-2 chemically modified with water-soluble polymers. J Biol Chem 1988, 263, 15064-70. 429 Katre, N. V.; Knauf, M. J.; Laird, W. J. Chemical modification of recombinant interleukin 2 by polyethylene glycol increases its potency in the murine Meth A sarcoma model. Proc Natl Acad Sci USA 1987, 84, 1487-91. 430 Vanwetswinkel, S.; Plaisance, S.; Zhi-yong, Z.; Vanlinthout, I.; Brepoels, K.; Lasters, I.; Collen, D.; Jespers, L. Pharmacokinetic and thrombolytic properties of cysteine-linked polyethylene glycol derivatives of staphylokinase. Blood 2000, 95, 936-42.

215

circulatory lifetime of the staphlokinase was increased through pegylation while thrombolytic

activity was maintained. The plasma clearance rates of the staphlokinase conjugate

decreased with increasing PEG molecular weight. Clinical trials revealed successful

restoration of circulation for patients suffering from acute myocardial infarction.431

Currently, strong interest exists in functionalizing polymers with the RGD protein to

promote cell adhesion for tissue scaffolds. The RGD protein selectively promotes cell

adhesion, while avoiding nonspecific adsorption of proteins. Furthermore, cell spreading, a

change in the cellular morphology occurs in the presence of the RGD coating, indicating cell

signaling has occurred. Hubbell et al. used a hetero-bifunctional PEG containing

N-hydroxysuccinimide and vinyl sulfone linkages to couple the RGD containing peptides via

cysteine linkages to the PEG and then to couple the PEG-RGD to poly(L-lysine).432

Surface grafting of biological molecules was achieved using the Michael addition

reaction.433 Model systems to achieve protein grafted surfaces were studied using PEG

acrylated surfaces coupled to cysteine containing proteins such as portions of the Platelet

factor 4 protein. A modification route beginning with thiol functionalized surfaces was also

pursued, however, the surface grafted thiols were unreactive.

431 Collen, M. D.; Sinnaeve, P.; Demarsin, E.; Moreau, H.; De Maeyer, M.; Jespers, L.; Laroche, Y.; van de Werf, F. Polyethylene glycol–derivatized cysteine-substitution variants of recombinant staphylokinase for single-bolus treatment of acute myocardial infarction. Circulation 2000, 102, 1766-72. 432 van de Vondele, S.; Voros, J.; Hubbell, J. A. RGD-grafted poly-L-lysine-graft-(polyethylene glycol) copolymers block non-specific protein adsorption while promoting cell adhesion. Biotech Bioeng 2003, 82, 784-90. 433 Heggli, M.; Tirelli, N.; Zisch, A.; Hubbell, J. A. Michael-type addition as a tool for surface functionalization. Bioconjug Chem 2003, 14, 967-73.

216

3.8.2 Coupling of Biological Molecules to Michael Addition Polymers

In addition to the Michael reaction as a strategy to couple synthetic polymers to

biological molecules, it is also useful in the synthesis of polymers that will be coupled to

biological molecules. Numerous Michael addition polymers are useful as precursors for

bioconjugates due to their biocompatibility and biodegradability. Poly(amido amine)s are

an excellent example of a biocompatible, biodegradable Michael addition polymers. Both

linear poly(amido amine)s and dendritic poly(amido amine)s (PAMAM) proved useful in

forming bioconjugates.

Ferruti et al. synthesized poly(amido amine) drug conjugates of the anticancer drug

mitomycin C, which was bound to pendant hydroxyl groups on the poly(amido amine).

In-vivo studies showed similar antitumor activity for the conjugate compared to mitomycin C

as well as lower toxicity values.434 Poly(amido amine) dendrimers were also used to

facilitate the release of the toxic anticancer drug 5-fluorouracil via covalent incorporation

onto the terminal amines on the dendrimer structure.435 Higher generation dendrimers

released larger amounts of 5-fluorouracil, with complete release occurring over the period of

about one week.

Glycodendrimers are dendrimers containing saccharide residues on the peripheral

functional groups. Glycodendrimer interactions with proteins are often more pronounced

than with individual saccharides due to increased “valency”. However, the density of

functional groups at the dendrimer surface may potentially lead to steric hindrance of the

434 Ferruti, P.; Marchisio, M. A.; Duncan, R. Poly(amido-amine)s: biomedical applications. Macromol Rapid Commun 2002, 23, 332-55. 435 Zhuo, R. X.; Du, B.; Lu, Z. R. In vitro release of 5-fluorouracil with cyclic core dendritic polymer. J Contr Rel 1999, 57, 249-57.

217

sugar groups. Meijer et al. introduced peripheral sugar groups at various distances from the

surface of PPI dendrimers using alkyl spacers of various lengths, thus reducing steric

congestion.436

3.9 Conclusions and Future Directions

This review outlined the current applications of the Michael addition to polymer

synthesis. The Michael addition reaction serves important roles in polymer synthesis,

allowing the development of novel polymers from diverse monomer feedstocks. Polymers

of numerous different topologies including linear, dendritic, hyperbranched and network

polymers are enabled. Both step growth and chain growth techniques are utilized. The

flexibility of the Michael reaction in terms of monomer functionality, solvent environment,

and conversion at ambient or near ambient temperature allows the production of sophisticated

macromolecular systems for technologically important applications. Other advantages

include a general lack of sensitivity to oxygen and the absence of low molar mass byproducts

which require removal.

The applications of Michael addition polymers are as diverse as their compositions and

topologies, ranging from networks for coatings and adhesives to linear, biodegradable

polymers for gene transfection or drug delivery. Several Michael addition polymers such as

poly(amido amine)s benefit from biocompatibility and non-toxic degradation products.

Michael addition also serves as a synthetic tool for coupling polymers with biological

436 Peerlings, H. W. I.; Nepogodiev, S. A.; Stoddart, J. F.; Meijer, E. W. Synthesis of spacer-armed glucodendrimers based on the modification of poly(propylene imine) dendrimers. Eur J Org Chem 1998, 9, 1879-86.

218

systems such as proteins and enzymes. The ability to carry out the Michael addition under

physiological conditions permits novel tissue replacements, cell scaffolds and direct

application.

One aspect of the Michael addition largely unused in polymer science is the ability to

carry out stereospecific Michael additions. The application of special catalysts to achieve

stereospecific Michael addition may yield polymers with improved biological applications

and potential crystallinity. Chirality is particularly important in biological systems including

recognition processes with proteins. Another likely future direction for Michael addition

polymerizations is the increased use of bio-based reactants. The number of bio-based

precursors entering the market and the multitude of functionalities available for Michael

addition chemistry are growing. Many of these materials are amenable to modification for

introduction into Michael addition systems. Furthermore, the tolerance of the Michael

reaction to protic impurities allows the use of less well-defined feed streams.

3.10 Acknowledgements

This material is based upon work supported by the US Army Research Laboratory and

US Army Research Office under grant number DAAD19-02-1-0275 Macromolecular

Architecture for Performance (MAP) MURI.

The authors would like to acknowledge the financial support of Rohm and Haas Company

and the Department of Energy (DE-FG36-04GO14317).

219

Chapter 4. Synthesis of Chain End Functionalized Multiple Hydrogen

Bonded Polystyrenes and Poly(alkyl acrylates) via Nitroxide

Mediated Radical Polymerization

(Mather, B.D.; Lizotte, J.R.; Long, T.E. Macromolecules 2004, 37(25), 9331-7) Reproduced

with permission. Copyright 2004, American Chemical Society

4.1 Abstract

Hydrogen bonding uracil functionalized polystyrenes and poly(alkyl acrylate)s were

synthesized via nitroxide mediated polymerization. Quantitative chain end functionalization

was achieved using novel uracil containing TEMPO- and DEPN-based alkoxyamine

unimolecular initiators. Polymerizations were conducted at 130 °C and yielded functionalized

homopolymers with narrow molecular weight distributions (Mw/Mn = 1.20) and predictable

molecular weights. Polymerizations of both n-butyl acrylate and styrene using the DEPN-

and TEMPO-based alkoxyamines resulted in molecular weight control over a wide range of

conversions. Terminal functionalization of poly(alkyl acrylate)s with hydrogen bonding

groups increased the melt viscosity, and as expected, the viscosity approached that of the

nonfunctional analogues as temperature was increased. The hydrogen bonding effect was also

evident in thermal (DSC) analysis and 1H NMR spectroscopic investigations, and low molar

mass polystyrenes exhibited glass transition temperatures that were consistent with a higher

apparent molar mass. 1H NMR spectroscopy confirmed the presence of a single hydrogen

220

bonding group at the chain terminus, which was consistent with a well-defined initiation

process for two families of novel alkoxyamines.

4.2 Introduction

Stable free radical polymerization (SFRP), which is often also described as nitroxide

mediated polymerization (NMP), is well established as a controlled radical polymerization

methodology. 437438

-439

440 In a similar fashion to other controlled radical polymerization

methodologies, the process relies on an equilibrium between dormant propagating chains and

a low concentration of propagating radicals. The relatively high rate of initiation relative to

propagation and the reduction of transfer or termination events through reversible capping of

the growing radical chain end has lead to the classification of this polymerization

methodology as “living”. The systematic variation of the monomer weight to the moles of

initiator leads to predictable molecular weights and relatively low polydispersities (Mw/Mn ~

1.20). Stable free radical polymerization offers functional group tolerance, which is typical

of radical polymerizations. This tolerance provides versatility that is often not easily

achieved with other living polymerization techniques and less stringent purification

techniques are required compared to living anionic polymerization. Moreover, stable free

437 Hawker, C.J.; Bosman, A.W.; Harth, E. New Polymer Synthesis by Nitroxide Mediated Living Radical Polymerizations. Chem. Rev. 2001, 101, 3661-88. 438 Matyjaszewski, K., Advances in controlled/living radical polymerization. American Chemical Society: Washington, 2003; Vol. 854, p 2-9. 439 Hawker, C. J.; Hedrick, J. L.; Malmstrom, E.; Trollsas, M.; Stehling, U. M.; Waymouth, R. M., Solvent-free polymerizations and processes: minimization of conventional organic solvents In ACS Symposium Series, Long, T. E.; Hunt, M. O., Eds. 1998; Vol. 713, pp 127-39. 440 Bisht, H. S.; Chatterjee, A. K. Living Free-Radical Polymerization-A Review. J. Macromol. Sci., Polym. Rev. 2001, 41, 139-73.

221

radical polymerization437-440 enables the synthesis of block, 441 graft, star 442 , 443 and

hyperbranched444 topologies in a similar fashion to other living polymerization processes.

Rizzardo et.al. initially described stable free radical polymerization445,446 and later

Georges et al. examined bimolecular initiators which primarily involved TEMPO

(2,2,6,6-tetramethylpiperidinyloxy), conventional radical initiators (AIBN, BPO), and

styrenic monomers. 447 This method proved very effective for styrenic monomers.

Furthermore, the typical reaction rates initially were quite slow, and often days were required

to reach high conversion. More recently, other monomers such as acrylates, dienes, and

acrylamides were successfully polymerized using nitroxides such as DEPN

(N-tert-butyl-N-(1-diethylphosphono-2,2-dimethylpropyl)-N-oxyl), which contains a

hydrogen alpha to the nitroxide functionality.448449450

- 451 Polymerizations, which utilized this

441 Robin, S.; Guerret, O.; Couturier, J. L.; Pirri, R.; Gnanou, Y. Synthesis and Characterization of Poly(styrene-b-n-butyl acrylate-b-styrene) Triblock Copolymers Using a Dialkoxyamine as Initiator. Macromolecules 2002, 35, 3844-8. 442 Pasquale, A. J.; Long, T. E. Synthesis of star-shaped polystyrenes via nitroxide-mediated stable free-radical polymerization. J. Polym. Sci.: Part A. Polym. Chem. 2001, 39, 216-23. 443 Bosman, A. W.; Vestberg, R.; Heumann, A.; Fréchet, J. M. J.; Hawker, C. J. A Modular Approach toward Functionalized Three-Dimensional Macromolecules: From Synthetic Concepts to Practical Applications. J. Am. Chem. Soc. 2003, 125, 715-28. 444 Hawker, C. J. "Living" Free Radical Polymerization: A Unique Technique for the Preparation of Controlled Macromolecular Architectures. Acc. Chem. Res. 1997, 30, 373-82. 445 Solomon, D.H.; Rizzardo, P.; Cacioli, P. Polymerization process and polymers produced thereby. U.S. Patent. 4581429, 1986. 446 Moad, G.; Rizzardo, E.; Solomon, D. H. Selectivity of the reaction of free radicals with styrene. Macromolecules 1982, 15, 909-14. 447 Veregin, R. P. N.; Georges, M. K.; Kazmaier, P. M.; Hamer, G. K. Free radical polymerizations for narrow polydispersity resins: electron spin resonance studies of the kinetics and mechanism. Macromolecules 1993, 26, 5316-20. 448 Benoit, D.; Chaplinski, V.; Braslau, R.; Hawker, C. J. Development of a Universal Alkoxyamine for "Living" Free Radical Polymerizations. J. Am. Chem. Soc. 1999, 121, 3904-20. 449 Diaz, T.; Fischer, A.; Jonquieres, A.; Brembilla, A.; Lochon, P. Controlled Polymerization of Functional Monomers and Synthesis of Block Copolymers Using a β-Phosphonylated Nitroxide. Macromolecules 2003, 36, 2235-41.

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family of nitroxides, exhibited greater propagation rates than the styrene / TEMPO systems,

and this observation was attributed to the lower C-ON bond strengths due to steric strain.451

Stable free radical polymerization is a premier method for obtaining chain end functionality

due to recent advances in alkoxyamine “unimolecular” initiator synthesis. Unimolecular

initiators have the added advantage over bimolecular initiator systems due to defined

stoichiometry between the initiating fragment and the nitroxide. This feature leads to better

control of molecular weight and polydispersity, 452 and many synthetic methods were

discovered earlier for the preparation of alkoxyamine unimolecular initiators. For example,

Wu et.al. conducted a radical capping reaction between AIBN initiated styrene and

TEMPO.453 An alternate method involved hydrogen abstraction from benzylic sites using

t-butyl peroxide and in-situ radical capping with nitroxide.452 Hawker 454 and

Schmidt-Naake455 have employed manganese complexes, e.g. Jacobsen’s catalyst, to directly

react styrene olefinic sites with nitroxides. Moreover, in a scheme that is reminiscent of

atom transfer radical processes, nitroxides also react with an activated halide through a

450 Benoit, D.; Harth, E.; Fox, P.; Waymouth, R. M.; Hawker, C. J. Accurate Structural Control and Block Formation in the Living Polymerization of 1,3-Dienes by Nitroxide-Mediated Procedures. Macromolecules 2000, 33, 363-70. 451 Le Mercier, C.; Lutz, J. F.; Marque, S.; Le Moigne, F.; Tordo, P.; Lacroix-Desmazes, P.; Boutevin, B.; Couturier, J. L.; Guerret, O.; Martschke, R.; Sobek, J.; Fischer, H., In ACS Symposium Series, American Chemical Society: Washington, 2000; Vol. 768, pp 108-22. 452 Hawker, C. J.; Barclay, G. G.; Orellana, A.; Dao, J.; Devonport, W. Initiating Systems for Nitroxide-Mediated "Living" Free Radical Polymerizations: Synthesis and Evaluation. Macromolecules 1996, 29, 5245-54. 453 Wang, D.; Bi, X.; Wu, Z. Convenient Synthesis and Application of a New Unimolecular Initiator. Macromolecules 2000, 33, 2293-5. 454 Dao, J.; Benoit, D.; Hawker, C.J. A versatile and efficient synthesis of alkoxyamine LFR initiators via manganese based asymmetric epoxidation catalysts J. Polym. Sci., Part A: Polym. Chem. 1998, 36, 2161-7. 455 Bothe, M.; Schmidt-Naake, G. An Improved Catalytic Method for Alkoxyamine Synthesis - Functionalized and Biradical Initiators for Nitroxide-Mediated Radical Polymerization. Macromol. Rapid Commun. 2003, 24, 609-13.

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copper promoted coupling reaction.456,457 The particular functionality of interest in our

work was multiple hydrogen bonding chain end functionality, which was easily accessed

using earlier synthetic strategies for unimolecular initiators.

Multiple hydrogen bonding has recently gained attention in the field of macromolecular

and supramolecular chemistry due to the pioneering work of Meijer, 458 Stadler, 459

Lehn460and others.461,462 The use of multiple hydrogen bonding sites in conjunction with

conventional oligomers and polymers has resulted in thermoreversible mechanical and

rheological properties which are tunable based on the strength of the hydrogen bond.461,462

For example, Meijer introduced a self-complementary 2-ureido-4[1H]-pyrimidone quadruple

hydrogen bonding array at the ends a trifunctional oligomeric poly(propylene

glycol-co-ethylene glycol) copolymer and a thermoreversible network with film forming

456 Diaz, T.; Fischer, A.; Jonquieres, A.; Brembilla, A.; Lochon, P. Controlled Polymerization of Functional Monomers and Synthesis of Block Copolymers Using a β-Phosphonylated Nitroxide. Macromolecules 2003, 36, 2235-41. 457 Matyjaszewski, K.; Woodworth, B. E.; Zhang, X.; Gaynor, S.; Metzner, Z. Simple and Efficient Synthesis of Various Alkoxyamines for Stable Free Radical Polymerization. Macromolecules 1998, 31, 5955-7. 458 Lange, R. F. M.; van Gurp, M.; Meijer, E. W. Hydrogen-bonded supramolecular polymer networks. J. Polym. Sci. Part A. Polym. Chem. 1999, 37, 3657-70. 459 Müller, M.; Dardin, A.; Seidel, U.; Balsamo, V.; Ivan, B.; Spiess, H. W.; Stadler, R. Junction Dynamics in Telechelic Hydrogen Bonded Polyisobutylene Networks. Macromolecules 1996, 29, 2577-83. 460 Berl, V.; Schmutz, M.; Krische, M.J.; Khoury, R.G.; Lehn, J-.M. Supramolecular Polymers Generated from Heterocomplementary Monomers Linked through Multiple Hydrogen-Bonding Arrays–Formation, Characterization, and Properties. Chem. Eur. J. 2002, 8, 1227-44. 461 Yamauchi, K.; Lizotte, J. R.; Long, T. E. Thermoreversible Poly(alkyl acrylates) Consisting of Self-Complementary Multiple Hydrogen Bonding. Macromolecules 2003, 36, 1083-8. 462 Yamauchi, K.; Lizotte, J. R.; Hercules, D. M.; Vergne, M. J.; Long, T. E. Combinations of Microphase Separation and Terminal Multiple Hydrogen Bonding in Novel Macromolecules. J Am Chem Soc 2002, 124, 8599-604.

224

capability and elastomeric mechanical properties was observed.458 Long462 and Coates463

have also investigated the introduction of pyrimidones in a random fashion in a copolymer

using both radical and coordination polymerization methods respectively. The hydrogen

bonding motif offers unique thermoreversibility and the influence on physical properties is

quite evident in melt rheology. This design strategy offers promise for improved melt

processability with equivalent polymer properties at temperatures below hydrogen bond

dissociations and also enables potentially recyclable thermoreversible networks.

In biological systems, hydrogen bonding plays an essential role in protein folding and in

maintaining the structure of DNA and RNA. For example, the reversibility of the hydrogen

bonds that are between base pairs in the DNA structure permits the transcription process.464

In protein folding, hydrogen bonds establish the α-helix and β-sheet secondary structures.

Introduction of nucleic acid base pairs (adenine, thymine, uracil, guanine, cytosine) into

polymers is achievable via numerous means such as post polymerization end group

functionalization of well-defined anionically synthesized polymers465 or conventional radical

polymers,466 synthesis of functionalized (meth)acrylic or vinyl monomers followed by

conventional radical homopolymerization467 or copolymerization,468,469 alternating radical

463 Reith, R. L.; Eaton, F. R.; Coates, W. G. Polymerization of Ureidopyrimidinone-Functionalized Olefins by Using Late-Transition Metal Ziegler-Natta Catalysts: Synthesis of Thermoplastic Elastomeric Polyolefins. Angew. Chem. Int. Ed. 2001, 40, 2153-6. 464 Nir, E.; Kleinermanns, K.; de Vries, M.S. Nature 2000, 408, 949-51. 465 Yamauchi, K.; Lizotte, J. R.; Long, T. E. Synthesis and Characterization of Novel Complementary Multiple-Hydrogen Bonded (CMHB) Macromolecules via a Michael Addition. Macromolecules 2002, 35, 8745-50. 466 Ilhan, F.; Galow, T. H.; Gray, M.; Clavier, G.; Rotello, V. M. Giant Vesicle Formation through Self-Assembly of Complementary Random Copolymers. J Am Chem Soc 2000, 122, 5895-6. 467 Inaki, Y. Synthetic nucleic acid analogs. Prog. Polym. Sci. 1992, 17, 515-70. 468 Khan, A.; Haddleton, D. M.; Hannon, M. J.; Kukulj, D.; Marsh, A. Hydrogen Bond Template-Directed Polymerization of Protected 5'-Acryloylnucleosides. Macromolecules 1999, 32, 6560-4.

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polymerization with maleic anhydrides, 470 living cationic and anionic ring-opening

polymerization of cyclic base pair derivatives471 or post-polymerization functionalization of

poly(ethylene imine) and polypeptides. 472 The incorporation of base pairs leads to

molecular recognition ability, 473 , 474 metal ligation,469 photocrosslinking (thymine),474

photoresists474,475 and selective chromatographic media. 474

The present work, which involves controlled radical polymerization, offers the

advantage of controlled molecular weights and uracil placement without strenuous anionic

techniques or potentially incomplete post polymerization modification. Hydrogen bonding

units that are comprised of the uracil nucleic acid base are introduced into styrenic and

acrylic polymers using a new family of functionalized initiators. The expected

self-association of these units was probed using a number of techniques including melt

rheology and 1H NMR spectroscopy.

469 Srivatsan, S. G.; Parvez, M.; Verma, S. Modeling of Prebiotic Catalysis with Adenylated Polymeric Templates: Crystal Structure Studies and Kinetic Characterization of Template-Assisted Phosphate Ester Hydrolysis. Chem. Eur. J. 2002, 8, 5184-91. 470 Han, M.J.; Park, S.M.; Park, J.Y.; Yoon, S.H. Polynucleotide analogs. 3. Synthesis, characterization, and physicochemical properties of poly(thymidylic acid) analogs. Macromolecules 1992, 25, 3534-9. 471 Inaki, Y.; Futagawa, H.; Takemoto, K. Polymerization of cyclic derivatives of uracil and thymine. J. Polym. Sci., Part A: Polym. Chem. 1980, 18, 2959-69 472 Overberger, C.G.; Inaki, Y. Graft copolymers containing nucleic acid bases and L-α-amino acids. J. Polym. Sci., Part A: Polym. Chem. 1979, 17, 1739-58. 473 Ilhan, F.; Galow, T. H.; Gray, M.; Clavier, G.; Rotello, V. M. Giant Vesicle Formation through Self-Assembly of Complementary Random Copolymers. J Am Chem Soc 2000, 122, 5895-6. 474 Inaki, Y. Synthetic nucleic acid analogs. Prog. Polym. Sci. 1992, 17, 515-70. 475 Han, M.J.; Chang, J.Y. Polynucleotide analogues. Adv. in Polym. Sci. 2000, 153, 1-36

226

4.3 Experimental

4.3.1 Materials

Copper powder (45 μm, 99%), copper (II) triflate (98%), and

2,2,6,6-tetramethylpiperidinyloxy (TEMPO, 98%) were obtained from Acros and used as

received. Copper (I) bromide (99.999%), 4,4’-dinonylbipyridine (dNbpy, 97%) and

6-chloromethyluracil (98%) were obtained from Aldrich and used as received. Styrene

(99%, Aldrich), n-butyl acrylate (99%, Aldrich), dimethyl sulfoxide (DMSO, 99.9%, Aldrich),

N,N-dimethyl formamide (DMF, 99%, EM Science) and

N,N,N’,N”,N”-pentamethyldiethylenetriamine (PMDETA, 99%, Aldrich) were distilled from

calcium hydride and stored under nitrogen at 0 ºC. DEPN was synthesized according to a

procedure in the earlier literature.476

4.3.2 Synthesis of Uracil-TEMPO Unimolecular Initiator

6-Chloromethyluracil (1.69 g, 10.5 mmol), TEMPO (1.64 g, 10.4 mmol) and dNbpy

(170 mg, 0.42 mmol) were dissolved in dimethyl sulfoxide (DMSO, 10 mL).

Dichloromethane (20 mL) and THF (10 mL) were added to the reaction mixture. The

solution was subjected to three freeze-pump-thaw degassing cycles, warmed to room

temperature, and cannulated into a nitrogen filled flask containing a stir bar, copper (II)

triflate (37 mg, 0.10 mmol), and copper powder (0.670 g, 10.6 mmol). The reaction mixture

was heated to 70 ºC and stirred vigorously for 24 h. The contents of the reaction were

476 Grimaldi, S.; Finet, J. P.; Le Moigne, F.; Zeghdaoui, A.; Tordo, P.; Benoit, D.; Fontanille, M.; Gnanou, Y. Acyclic β-Phosphonylated Nitroxides: A New Series of Counter-Radicals for "Living"/Controlled Free Radical Polymerization. Macromolecules 2000, 33, 1141-7.

227

precipitated into water, gravity filtered, and washed with water. The resultant product was

dissolved in acetone and purified using flash chromatography on a silica column. The

acetone was removed using rotary evaporation and the product was dried under high vacuum

at room temperature for 24 h. Uracil-TEMPO was obtained as a white solid (mp 205-207 ºC)

in 24% yield. 1H NMR (400 MHz, CDCl3), 1.1-1.6 ppm (br multiplet, 18H from TEMPO

including methyls at 1.1 ppm), 4.6 ppm (d, J = 1.2 Hz, N-O-CH2-C=C: 2H), 5.6 ppm (br s,

C=CH-C=O: 1H), 8.5 ppm (br, N-H: 2H). 13C NMR (100 MHz, DMSO-d6), 16.9 ppm, 20.3

ppm, 31.2 ppm, 32.8 ppm (TEMPO 2º and 1º carbons), 60.1 ppm (TEMPO quaternary

carbons), 73.6 ppm (CH2-O-N), 96.8 ppm (C=CH-C=O), 151.8 ppm (NH-C=O-NH), 153.0

ppm (C=CH-C=O), 164.5 ppm (C=CH-C=O). FAB MS: m/z = 282.1794 amu

(experimental), m/z = 282.1818 amu (theoretical).

4.3.3 Synthesis of Uracil-DEPN Unimolecular Initiator

6-Chloromethyluracil (1.82 g, 11.4 mmol), DEPN (3.00 g, 10.2 mmol) and PMDETA

(3.51 g, 20.4 mmol) were dissolved in DMSO (20 mL). Dichloromethane (40 mL) was

added to the reaction mixture. The solution was subjected to three freeze-pump-thaw

degassing cycles, warmed to room temperature, and transferred under nitrogen into a nitrogen

filled flask containing a stir bar, copper (I) bromide (1.16 g, 8.2 mmol), and copper powder

(0.51 g, 8.2 mmol). The reaction mixture was stirred vigorously for 24 h at ambient

temperature. Dichloromethane (300 mL) was added to the reaction mixture and the contents

were washed with deionized water 5 times, dried over sodium sulfate, and decanted. The

solvent was removed using rotary evaporation at ambient temperature and the resulting green

228

oil was subjected to column chromatography on silica, and eluting with acetone. The acetone

was removed using rotary evaporation and the product was dried under high vacuum at room

temperature for 24 h. Uracil-DEPN was obtained as a white solid (mp 137-141 ºC) in 71%

yield. 1H NMR (400 MHz, CDCl3), 1.16 ppm (two s, two C(CH3)3: 18H ), 1.2-1.36 ppm (m,

ethoxy CH3: 6H), 3.30 ppm (d, JP-H = 25 Hz -N-CHC(CH3)3-PO(OEt)2: 1H), 3.95-4.22 ppm

(m, ethoxy CH2: 4H), 4.37 ppm and 4.91 ppm (two d, J = 11 Hz, CH2-O-N: 2H), 5.48 ppm

(br s, C=CH-C=O: 1H), 8.31 ppm (br, C-NH-C=O), 11.79 ppm (br, O=C-NH-C=O: 1H). 13C

NMR (100 MHz, CDCl3), 16.2 ppm (ethoxy CH3), 27.7 ppm (N-C(CH3)3), 30.3 ppm

(C-C(CH3)3), 36.3 ppm (C-C(CH3)3), 60.3 ppm, 61.7 ppm (P-O-CH2, JC-P = 144 Hz), 62.5

(N-C(CH3)3), 67.6 ppm and 69.0 ppm (N-CH-P, JC-P = 140 Hz), 73.5 ppm (CH2-O-N), 99.6

ppm (C=CH-C=O), 150.0 ppm (NH-C=O-NH), 151.1 ppm (C=CH-C=O), 164.2 ppm

(C=CH-C=O). FAB MS: m/z = 420.2271 amu (experimental), m/z = 420.2263 amu

(theoretical).

4.3.4 Polymerizations of Styrene Using Uracil-TEMPO

A 100-mL round-bottomed flask containing a magnetic stirring bar was charged with

Uracil-TEMPO (100 mg, 0.35 mmol), sealed with a septum-capped three-way glass adaptor

connected to a vacuum line, and flushed through repeated vacuum / nitrogen cycles before

distilled styrene monomer (30 mL, 259 mmol) was introduced via syringe. The solution

was further degassed with multiple freeze-pump-thaw cycles using a dry ice / isopropanol

bath and warmed to room temperature. The in-situ FTIR probe was inserted into a 100-mL

three-necked flask, and the system was septum sealed and flushed with nitrogen for 30

229

minutes. The degassed solution was transferred under an inert atmosphere into the

three-necked flask and immersed in an oil bath, which was maintained at 130 ºC. Samples

(2-3 mL) were removed from the reaction at hourly intervals using a syringe. All samples,

as well as the final product, were isolated via precipitation into a large excess of isopropanol

after first diluting with an equal volume of THF, and subsequently dried overnight under

vacuum at elevated temperature (~80-100 ºC). The final polymer product had Mn = 47,200

g/mol and Mw/Mn = 1.22 (SEC MALLS), which agrees well with the molecular weight

calculated based on monomer conversion as measured using in-situ FTIR spectroscopy

(47,100 g/mol, 62% conversion).

4.3.5 Polymerizations of n-Butyl Acrylate Using Uracil-DEPN

Polymerizations involving n-butyl acrylate and Uracil-DEPN were conducted in an

analogous fashion to those involving styrene and Uracil-TEMPO, however, an additional 0.5

equivalents of DEPN were added to the reaction mixture prior to degassing. A small excess

of nitroxide was shown earlier to improve control of nitroxide mediated acrylate

polymerizations.477,478 Uracil-DEPN initiator (120 mg, 0.29 mmol) and DEPN (42 mg, 0.14

mmol) were added to a 100-mL round bottom flask containing a magnetic stirring bar. The

flask was sealed with a septum-capped three-way glass adaptor, connected to a vacuum line,

and flushed through repeated vacuum / nitrogen cycles before distilled n-butyl acrylate

477 Benoit, D.; Grimaldi, S.; Robin, S.; Finet, J. P.; Tordo, P.; Gnanou, Y. Kinetics and Mechanism of Controlled Free-Radical Polymerization of Styrene and n-Butyl Acrylate in the Presence of an Acyclic β-Phosphonylated Nitroxide. J. Am. Chem. Soc. 2000, 122, 5929-39. 478 Lacroix-Desmazes, P.; Lutz, J. F.; Chauvin, F.; Severac, R.; Boutevin, B. Living Radical Polymerization: Use of an Excess of Nitroxide as a Rate Moderator. Macromolecules 2001, 34, 8866-71.

230

monomer (28.5 mL, 200 mmol) and distilled DMF (10 mL) were introduced via syringe.

The solution was further degassed with multiple freeze-pump-thaw cycles using a dry ice /

isopropanol bath and warmed to room temperature. The in-situ FTIR probe was inserted

into a 100-mL three-neck flask, and the system was septum sealed and flushed with nitrogen

for 30 minutes. The degassed solution was transferred under nitrogen atmosphere into the

three-necked flask and immersed in an oil bath, which was maintained at 130 ºC. Samples

(2-3 mL) were removed from the reaction at hourly intervals using a syringe. All samples,

as well as the final product, were isolated via precipitation into a large excess of

methanol/water (9:1), and subsequently vacuum dried overnight at elevated temperature

(~80-100 ºC). The final polymer product had Mn = 44600 and Mw/Mn = 1.17 (SEC

MALLS), which agrees well with the molecular weight calculated from monomer conversion

(42700, 48% conversion).

4.3.6 Polymer Characterization

Size exlusion chromatography (SEC) was performed at 40 °C in chloroform or THF at a

flow rate of 1 mL/min using a Waters size exclusion chromatographer equipped with an

autosampler, three 5 μm PLgel Mixed-C columns, a Waters 2410 refractive index (RI)

detector, and a miniDAWN multiangle laser light scattering (MALLS) detector operating at

690 nm, which was calibrated with polystyrene standards. The refractive index increment

(dn/dc) was calculated online. SEC of uracil-polystyrenes in N-methylpyrrolidone

containing 0.05 M LiBr was performed using a Waters size exclusion chromatographer

equipped with a 2414 refractive index detector, which was calibrated using polystyrene

231

standards. In-situ FTIR spectroscopic analysis was performed using an ASI ReactIR 1000

attenuated total reflectance (ATR) spectrometer.200, 201 Differential scanning calorimetry

(DSC) was performed under a nitrogen flush at a heating rate of 10 ºC/min on a PE Pyris 1

instrument, which was calibrated using indium (mp = 156.60 ºC) and zinc (mp = 419.47 ºC)

standards. Glass transition temperatures were measured as the mid-point of the transition.

Thermogravimetric analysis (TGA) was performed under a nitrogen atmosphere at a heating

rate of 10 ºC/min using a TA Instruments Hi-Res TGA 2950. NMR spectroscopic data was

collected in either CDCl3 or DMSO-d6 on a Varian 400 MHz spectrometer at ambient

temperature. Melt rheology was performed on a stress-controlled, TA Instruments

Advanced Rheometer 1000 using a 1 kPa oscillatory stress and a 62.45 rad/s shear rate in a

25 mm diameter parallel plate geometry with a plate separation distance of 1 mm.

4.4 Results and Discussion

4.4.1 Uracil-TEMPO and Uracil-DEPN Unimolecular Initiator Syntheses

The Uracil-TEMPO unimolecular initiator was synthesized analogously to non-

hydrogen bonding alkoxyamines discussed in the literature (Figure 4.1).479 A copper (I)

species, which is generated from Cuº and copper (II) triflate, reductively cleaves the C-Cl

bond in 6-chloromethyluracil, and TEMPO efficiently caps the resulting allylic radical in

solution. A similar approach was used for Uracil-DEPN synthesis, however, copper (I)

479 Matyjaszewski, K.; Woodworth, B. E.; Zhang, X.; Gaynor, S.; Metzner, Z. Simple and Efficient Synthesis of Various Alkoxyamines for Stable Free Radical Polymerization. Macromolecules 1998, 31, 5955-7.

232

bromide was introduced rather than generated in-situ.480 These synthetic methods are

convenient, but are limited to activated halides, such as benzylic halides or α-halocarbonyl

compounds, due to the instability of the radical generated from non-activated alkyl halides.

In this work, it was demonstrated that the conjugated enone activates the chloride on

6-chloromethyluracil, and enables the one-step synthesis of a unimolecular initiator

containing a site for hydrogen bonding.

480 Diaz, T.; Fischer, A.; Jonquieres, A.; Brembilla, A.; Lochon, P. Controlled Polymerization of Functional Monomers and Synthesis of Block Copolymers Using a β-Phosphonylated Nitroxide. Macromolecules 2003, 36, 2235-41.

233

HN

NH

O

OCl

HN

NH

O

OO

N

HN

NH

O

O

TEMPO

Cu (II) triflate / Cuº dNbpy 70 ºC

Styrene130 ºC

n

ON

HN

NH

O

OCl

HN

NH

O

OO

N PO

EtOOEt

HN

NH

O

O

OO

nBu

DEPN

n

DEPN

Cu(I)BrPMDETAr.t., 24 h

n-butyl acrylate

DEPN, DMSO130 篊

Figure 4.1. Synthesis and polymerization from Uracil-TEMPO and Uracil-DEPN.

234

4.4.2 Polymerizations of Styrene and n-Butyl Acrylate Using the Uracil Based Initiators

Polystyrenes and poly(n-butyl acrylates) with molecular weights ranging from 4500

g/mol to 42000 g/mol with narrow molecular weight distributions were synthesized using

Uracil-TEMPO and Uracil-DEPN. The polymerization reactions were colorless and

exhibited significant increases in viscosity but typically were not allowed to vitrify. The

polymer products were colorless and similar in appearance to polymers that were prepared

using conventional azo or peroxide initiators. In some experiments, polymerizations were

performed using 25 vol % DMSO or DMF to study the effect of hydrogen bond screening

solvents on the polymerization, however, statistically significant effects on the kinetics or the

molecular weight evolution with conversion were not observed.

Good agreement was obtained between experimental molecular weights and

molecular weights calculated from monomer conversion as measured using in-situ FTIR

spectroscopy (gstyrene / molinitiator × % conversion) (Table 4.1). Typically, low conversions

(~50%) were targeted due to the risk of side reactions at higher conversion such as nitroxide

degradation and chain termination which can lead to broadened polydispersities.481 1H

NMR spectroscopy was utilized to verify the presence of the uracil end group through

comparison of the NMR number average molecular weights with SEC results (Table 4.2).

In the case of polystyrenes, the ratio of the integration of the aromatic protons to the

integration of the alkene proton of the uracil end group allowed the accurate calculation of

NMR number average molecular weights for values less than 25000. For poly(n-butyl

481 Moffat, K.; Hamer, G. K.; Georges, M. K. Stable Free Radical Polymerization Process: Kinetic and Mechanistic Study of the Thermal Decomposition of MB-TMP Monitored by NMR and ESR Spectroscopy. Macromolecules 1999, 32, 1004-12.

235

acrylate)s, the ratio of the integration of the CH2 protons that are α to the acrylate ester to the

integration of the alkene proton of the uracil end group was used to calculate molecular

weights. Similar calculations were performed using protons α to the nitroxide end groups,

and comparable results were obtained. In the case of uracil functionalized polystyrenes, 1H

NMR spectroscopy also allowed the verification of TEMPO methyl resonances near 0.5 ppm.

236

Table 4.1. Target and experimental molecular weights for polystyrenes and poly(n-butyl

acrylate)s synthesized using Uracil-TEMPO and Uracil-DEPN.

Monomer/Initiator Targeta Mn GPCb Mn Mw/Mn Styrene/U-TEMPO 7100 8000 1.10 Styrene/U-TEMPO 13200 13000 1.27 Styrene/U-TEMPO 27000 25200 1.26 Styrene/U-TEMPO 36500 39800 1.26 Styrene/U-TEMPO 43700 45700 1.21 Styrene/U-TEMPO 69900 75200 1.27 Styrene/U-TEMPO 84400 99200 1.28

nBA/U-DEPN 4100 5900 1.20 nBA/U-DEPN 9100 9800 1.22 nBA/U-DEPN 11700 13700 1.12 nBA/U-DEPN 19500 19100 1.12 nBA/U-DEPN 27000 26100 1.11 nBA/U-DEPN 35600 33300 1.18 nBA/U-DEPN 42500 44600 1.17

a Target = % conversion × (gmonomer / molesinit) (conversion measured using in-situ FTIR) b MALLS, 40 ºC

237

Table 4.2. Uracil functionalized polystyrene and poly(n-butyl acrylate) molecular weights

determined using both GPC and NMR.

Monomer/Initiator GPCa Mn NMRb Mn Mw/Mn Styrene/U-TEMPO 4500 4800 1.07 Styrene/U-TEMPO 7800 7000 1.04 Styrene/U-TEMPO 10500 9400 1.04 Styrene/U-TEMPO 14600 14400 1.05 Styrene/U-TEMPO 21600 21500 1.26

nBA/U-DEPN 5900 5500 1.20 nBA/U-DEPN 13700 13400 1.12 nBA/U-DEPN 16700 15300 1.09 nBA/U-DEPN 19100 21000 1.12 nBA/U-DEPN 26100 28500 1.11 nBA/U-DEPN 33000 33800 1.14 nBA/U-DEPN 40600 48800 1.19

a MALLS, 40 ºC b 400 MHz, CDCl3, r.t., using uracil alkene proton.

238

4.4.3 In-situ FTIR Monitoring of Polymerization Kinetics

In-situ FTIR spectroscopy is a powerful, state-of-the-art analytical technique for

monitoring numerous organic reactions. The primary strengths of this technique include

kinetic analyses, determining reaction order, and obtaining real-time conversion information.

The ASI ReactIR instrument is equipped with a diamond-composite/stainless steel probe,

which allows the monitoring of reactions under a wide range of pressures (up to 100 psi),

temperatures (up to 300 ºC) and aggressive reagents. Our research laboratories have

devoted significant attention to the kinetic analyses of nitroxide-mediated polymerization

using in-situ FTIR spectroscopy.482,483

The polymerization kinetics of styrene and n-butyl acrylate using the uracil based

initiators at 130 ºC revealed pseudo-first order polymerization kinetics, which is expected for

radical polymerizations, and is indicative of a constant number of propagating centers (Figure

4.2). The absorbance at 907 cm-1, which corresponds to the vinyl CH2 wag of styrene, was

used to determine the styrene concentration based on a calibration curve that was constructed

from a range of styrene / polystyrene compositions at 130 ºC. The average observed rate

constant (kobs = kp) for Uracil-TEMPO initiated styrene polymerization of approximately 3.0

x 10-5 s-1 was 50% higher than literature values for TEMPO mediated polymerization of

styrene at 132 ºC using a similar method.484 It is possible that this difference arises from the

482 Pasquale, A. J.; Lizotte, J. R.; Williamson, D. T.; Long, T. E. The allure of "molecular videos": In-situ infrared spectroscopy of polymerization processes. Polym. News 2002, 27, 272-83. 483 Lizotte, J. R.; Erwin, B. M.; Colby, R. H.; Long, T. E. Investigations of thermal polymerization in the stable free-radical polymerization of 2-vinylnaphthalene. J. Polym. Sci., Part A: Polym. Chem. 2002, 40, 583-90. 484 Pasquale, A. J.; Long, T. E. Real-Time Monitoring of the Stable Free Radical Polymerization of Styrene via in-Situ Mid-Infrared Spectroscopy. Macromolecules 1999, 32, 7954-7.

239

use of a unimolecular initiating system in this work as opposed to the bimolecular reaction

previously employed since stoichiometric mismatch in the latter case could lead to excess

nitroxide. Furthermore, the use of a calibration curve in analyzing the in-situ FTIR

spectroscopic data may have also contributed to this difference since calibration was not used

in the cited reference. Interestingly, for various ratios of Uracil-TEMPO to styrene, nearly

identical rate constants were obtained (Table 4.3), which is consistent with the observations

of Fischer485 and others,486 that the amount of initiator did not affect the polymerization rate.

Similar equilibrium concentrations of active radicals exist in these polymerizations, however,

these active radicals are in equilibrium with differing numbers of dormant chains, which

leads to different molecular weights at various [M]:[I] ratios.

485 Fischer, A.; Brembilla, A.; Lochon, P. Nitroxide-Mediated Radical Polymerization of 4-Vinylpyridine: Study of the Pseudo-Living Character of the Reaction and Influence of Temperature and Nitroxide Concentration. Macromolecules 1999, 32, 6069-72. 486 Fukuda, T.; Terauchi, T.; Goto, A.; Ohno, K.; Tsujii, Y.; Miyamoto, T. Mechanisms and Kinetics of Nitroxide-Controlled Free Radical Polymerization. Macromolecules 1996, 29, 6393-8.

240

0

0.2

0.4

0.6

0.8

0 1 2 3 4 5

time (h)

ln(M

o/M)

Uracil-TEMPO / StyreneUracil-DEPN / nBA

kobs = 3.7x10-5 s-1

kobs = 2.7x10-5 s-1

Figure 4.2. In-situ FTIR kinetic plot of styrene and n-butyl acrylate polymerizations using

Uracil-TEMPO and Uracil-DEPN at 130 ºC. [Styrene]:[U-TEMPO] = 1460 (bulk),

[nBA]:[U-DEPN] = 695 (25 vol% DMSO).

241

Table 4.3. Polymerization rate constants for various styrene to Uracil-TEMPO ratios.

Moles monomer : Moles initiator

kobsa (s-1)

366:1 3.02 x 10-5 488:1 3.12 x 10-5 732:1 2.97 x 10-5 1460:1 2.69 x 10-5 1740:1 3.06 x 10-5

a Determined by in-situ FTIR, 130 ºC

242

During in-situ FTIR spectroscopic investigations of the n-butyl acrylate polymerizations,

calibration curves were obtained for known mixtures of n-butyl acrylate and poly(n-butyl

acrylate) at an absorbance maximum centered at 968 cm-1. The rate constant of

polymerization of n-butyl acrylate using the Uracil-DEPN unimolecular initiator in DMSO

was 3.7 x 10-5 s-1 at an initiator concentration of 7.4 mM. This rate constant appears low

considering that DEPN based styrene polymerizations were shown earlier to proceed at

significantly faster rates than analogous TEMPO mediated polymerizations.487 Faster rate

constants were reported for n-butyl acrylate polymerizations at a lower temperature (120 ºC)

without additional DEPN (~1 x 10-4 s-1).488 It is presumed that the slower kinetics in this

work is due to the introduction of 0.5 equivalents of additional nitroxide relative to initiator

into the polymerizations, which is known to slow polymerization kinetics.489,490

The evolution of molecular weight with conversion was obtained through a combination

of sampling techniques and in-situ FTIR spectroscopy (Figure 4.3). In the case of both

unimolecular initiators, number average molecular weights increased in proportion to

monomer conversion, with a proportionality constant equal to grams of monomer divided by

moles of initiator.

487 Grimaldi, S.; Finet, J. P.; Le Moigne, F.; Zeghdaoui, A.; Tordo, P.; Benoit, D.; Fontanille, M.; Gnanou, Y. Acyclic β-Phosphonylated Nitroxides: A New Series of Counter-Radicals for "Living"/Controlled Free Radical Polymerization. Macromolecules 2000, 33, 1141-7. 488 Benoit, D.; Grimaldi, S.; Robin, S.; Finet, J. P.; Tordo, P.; Gnanou, Y. Kinetics and Mechanism of Controlled Free-Radical Polymerization of Styrene and n-Butyl Acrylate in the Presence of an Acyclic β-Phosphonylated Nitroxide. J. Am. Chem. Soc. 2000, 122, 5929-39. 489 Benoit, D.; Chaplinski, V.; Braslau, R.; Hawker, C. J. Development of a Universal Alkoxyamine for "Living" Free Radical Polymerizations. J. Am. Chem. Soc. 1999, 121, 3904-20. 490 Lacroix-Desmazes, P.; Lutz, J. F.; Chauvin, F.; Severac, R.; Boutevin, B. Living Radical Polymerization: Use of an Excess of Nitroxide as a Rate Moderator. Macromolecules 2001, 34, 8866-71.

243

0

10000

20000

30000

40000

50000

60000

0 20 40 60 80Percent Conversion (FTIR)

Mn (

g/m

ol)

Uracil-TEMPO / Styrene

Uracil-DEPN / nBA

Figure 4.3. Evolution of molecular weight with conversion for the polymerizations of styrene

and n-butyl acrylate from Uracil-TEMPO and Uracil-DEPN at 130 ºC with 25 vol% DMSO.

[Styrene]:[U-TEMPO] = 730, [nBA]:[U-DEPN] = 695.

244

4.4.4 Characterization of Hydrogen Bonding Using 1H NMR Spectroscopy

Dilution affects the position of the equilibrium between individual and associated

hydrogen bonding groups in the system, as is suggested in the definition of the association

constant. Diluting a system composed of associating species should shift the equilibrium

toward the unassociated species. Thus, changing the concentration of the uracil end group

in CDCl3 induced a change in the degree of hydrogen bonding which resulted in a change in

the chemical shift of one of the N-H protons. Rather than changing the concentration of the

polymer in solution, samples of uracil functionalized polystyrene of different molecular

weights were dissolved in chloroform-d at an identical concentration of 10.4 wt%. This

relatively high solution concentration was chosen due to the ease of observing the N-H

protons in 1H NMR spectroscopy as concentration increases. As the molecular weight of

the polystyrenes increased, the chemical shift decreased, which indicated less hydrogen

bonding interaction for the higher molecular weight polymer chains due to the lower chain

end concentration (Figure 4.4). Attempts to fit the chemical shift vs. concentration data to

dimeric self-association models were unsuccessful, which suggested a higher stoichiometry

for the complex.491 However, the trend permitted the construction of a calibration curve for

prediction of molecular weights for these polymers based on 1H NMR spectroscopy. The

uracil group is known to associate in several possible geometries due to the presence of both

imide and lactam units in the uracil ring.492 This is expected to lead to an association

491 Chen, J. S.; Shirts, R. B. Iterative determination of the NMR monomer shift and dimerization constant in a self-associating system. J. Phys. Chem. 1985, 89, 1643-46 492 Beijer, F. H.; Sijbesma, R. P. V., J.A.J.M.; Meijer, E. W. K., H; Spek, A.L. Hydrogen-Bonded Complexes of Diaminopyridines and Diaminotriazines: Opposite Effect of Acylation on Complex Stabilities. J. Org. Chem. 1996, 61, 6371-80.

245

constant that reflects a combination of several complexes, but this should not hinder the

measurement of the association constant.

246

7.5

8.0

8.5

9.0

9.5

10.0

0 20 40 60 80

Mn (kg/mol) (GPC)

δ (p

pm)

Figure 4.4. Chemical shift of uracil N-H protons as a function of molecular weight in CDCl3

at 10.4 wt%.

247

Earlier observations of associations during SEC analysis for hydrogen bonding

polymers has prompted SEC in more polar eluents.493 Comparison of SEC measurements of

uracil polystyrenes in NMP containing LiBr, a hydrogen bond screening agent, versus

chloroform suggested that significant hydrogen bonding did not occur during the SEC

analysis. Furthermore, the agreement of the SEC molecular weight data with target

molecular weights as well as those obtained via NMR spectroscopic analysis suggest the

absence of associations at the concentrations employed in SEC.

4.4.5 Characterization of Hydrogen Bonding Using Melt Rheology

The low glass transition temperature of poly(n-butyl acrylate) permits melt rheology

experiments over a temperature range that spans both associated and dissociated states of the

hydrogen bonding group, as the thermal dissociation of hydrogen bonding groups may occur

at temperatures from 50 ºC to 130 ºC.494495496

- 497 Melt rheology was performed on two samples

of poly(n-butyl acrylate), one possessing the uracil end group (Mn = 25,400 g/mol, Mw/Mn =

1.17) and another possessing a 1-phenylethyl group (Mn = 24000 g/mol, Mw/Mn = 1.16).

Zero shear viscosities were collected over a temperature range from 20 ºC to 100 ºC (Figure

493 Zheng, W.; Angelopoulos, M.; Epstein, A. J.; MacDiarmid, A. G. Experimental Evidence for Hydrogen Bonding in Polyaniline: Mechanism of Aggregate Formation and Dependency on Oxidation State. Macromolecules 1997, 30, 2953-55. 494 Yamauchi, K.; Lizotte, J. R.; Hercules, D. M.; Vergne, M. J.; Long, T. E. Combinations of Microphase Separation and Terminal Multiple Hydrogen Bonding in Novel Macromolecules. J Am Chem Soc 2002, 124, 8599-604. 495 Yamauchi, K.; Lizotte, J. R.; Long, T. E. Thermoreversible Poly(alkyl acrylates) Consisting of Self-Complementary Multiple Hydrogen Bonding. Macromolecules 2003, 36, 1083-8. 496 Müller, M.; Dardin, A.; Seidel, U.; Balsamo, V.; Ivan, B.; Spiess, H. W.; Stadler, R. Junction Dynamics in Telechelic Hydrogen Bonded Polyisobutylene Networks. Macromolecules 1996, 29, 2577-83 497 Lillya, C. P.; Baker, R. J.; Huette, S.; Winter, H. H.; Lin, H.-G.; Shi, J.; Dickinson, L. C.; Chien, J. C. W. Linear Chain Extension through Associative Termini. Macromolecules 1992, 25, 2076-80.

248

4.5). Melt viscosity enhancements were clearly observed for the uracil functionalized

polyacrylate with nearly equivalent molecular weight. However, there was a stronger

temperature dependence for the melt viscosity of the uracil functionalized poly(n-butyl

acrylate), and dissociation of the hydrogen bonding groups appeared near 80 ºC. An

Arrhenius analysis of the zero shear viscosities revealed a higher flow activation energy for

the uracil functionalized acrylate (54 kJ/mol vs. 48 kJ/mol) (Figure 4.6). The correlation

coefficient for the linear fit used to calculate the activation energy was 0.996 in both cases.

Based on the fact that flow activation energy is independent of molecular weight,498 the data

suggests a more than dimeric association of the uracil end groups.

498 Wilkes, G. L. An overview of the basic rheological behavior of polymer fluids with an emphasis on polymer melts. J. Chem. Educ. 1981, 58, 880-92.

249

0

50

100

150

200

250

300

60 80 100 120 140

T-Tg (ºC)

(Pa-

s)

Non functional nBAUracil-nBA

Figure 4.5. Zero-shear melt viscosities for uracil functionalized poly(n-butyl acrylate) (Mn

= 25400, Mw/Mn = 1.17) and non functionalized poly(n-butyl acrylate) (Mn = 24000, Mw/Mn

= 1.16).

η o

250

Figure 4.6. Arrhenius analysis of the melt rheology data depicting the flow activation

energies for functionalized and non functionalized poly(n-butyl acrylate).

251

4.4.6 Thermal Analysis of Uracil Polystyrenes

Thermogravimetric analysis (TGA) was performed on the lower molecular weight

uracil functionalized polystyrene samples (Mn < 15000 g/mol). A two-step degradation

process was observed in each case (Figure 4.7). The weight loss during the first step (195 -

250 ºC) decreased with increasing molecular weight. A two-step degradation process is not

normally observed with non-functional polystyrene, but was reported earlier for

TEMPO-functionalized polystyrene at similar temperatures. 499 In order to determine

whether the 1st stage degradation involved the loss of TEMPO, an isothermal degradation

experiment was performed in which a uracil functionalized polystyrene (Mn = 7800 g/mol,

Mw/Mn = 1.04, SEC MALLS) was heated to 230 ºC for 30 min under nitrogen inside the TGA

furnace. The sample remained completely soluble in CDCl3, but a slightly brown color

developed, and the 1H NMR spectrum indicated the presence of the uracil group in the

polymer (the uracil alkene proton at 5.4 ppm) and the loss of the TEMPO group (the geminal

dimethyl protons at 0.5 ppm, and benzylic ether proton at 4.1 ppm). The molecular weight

calculated using the uracil alkene proton peak (Mn = 7500 g/mol) was similar to the value

obtained from 1H NMR spectroscopy before degradation (Mn = 7000 g/mol). Gel permeation

chromatography showed that the molecular weight had increased slightly and that the

distribution had also broadened (Mn = 8100, Mw/Mn = 1.27), possibly due to coupling events.

A resonance in the spectrum for the degraded polymer at 3.1 ppm likely represents benzylic

protons at head to head linkages formed during styrenic radical combination.499

499 Roland, A. I.; Schmidt-Naake, G. Thermal degradation of polystyrene produced by nitroxide-controlled radical polymerization. J. Anal. App. Pyrol. 2001, 58-9, 143-54.

252

Figure 4.7. Thermogravimetric and derivative traces for a polystyrene synthesized from

Uracil-TEMPO (Mn = 4500, Mw/Mn = 1.07).

253

A series of uracil functionalized polystyrenes with molecular weights between 5000 and

15000 g/mol were subjected to DSC analysis in order to determine their glass transition

temperatures. All samples had approximately the same glass transition temperature (Table

4.4), despite the fact that molar masses were below 15000 g/mol, where non-associating end

groups typically contribute to a lower glass transition temperature.500 Lin has demonstrated

that the glass transition temperature of polystyrene decreases markedly as a function of molar

mass below Me.501 The data suggests that the higher end group concentrations for lower

molecular weight samples resulted in larger Tg enhancements. Similar behavior was

observed in UPy functionalized polystyrenes.1

500 Fetters, L. J.; Lohse, D. J.; Milner, S. T. Packing Length Influence in Linear Polymer Melts on the Entanglement, Critical, and Reptation Molecular Weights. Macromolecules 1999, 32, 6847-51. 501 Lin, Y. H. Entanglement and the molecular weight dependence of polymer glass transition temperature. Macromolecules 1990, 23, 5292-94.

254

Table 4.4 Glass transition temperatures for various uracil functionalized polystyrenes with

molecular weights below the critical molecular weight.

Mn (GPC a) Tg b (ºC)

4500 101 7800 102 10500 102 14600 101

a MALLS, CHCl3, 40 ºC b DSC: 10 ºC/min, N2, 2nd heat

255

4.5 Conclusion

Novel uracil-containing alkoxyamines containing both TEMPO and DEPN were

synthesized and used in the stable free radical polymerization of styrene and n-butyl acrylate.

The resulting hydrogen bonding polymers exhibited narrow molecular weight distributions

(Mw/Mn ~ 1.20) and controlled molecular weights, which are characteristic of stable free

radical polymerizations. Linear progression of number average molecular weight with

conversion was observed. The rate constant of n-butyl acrylate polymerization (3.7 x 10-5

s-1) was slightly greater than that for styrene polymerization (3.0 x 10-5 s-1), however, it was

lower than typical literature values probably due to the quantity of excess nitroxide present.

Also, the styrene polymerization rate constant was higher than literature values possibly due

to excess nitroxide which may be present in bimolecular systems, but absent in unimolecular

initiation.

Characterization of the polymers using 1H NMR and melt rheology demonstrated the

presence of the hydrogen bonding interaction. Furthermore, a stronger temperature

dependence of melt viscosity was observed with uracil functionalized poly(n-butyl acrylate)s.

Thermogravimetric analysis combined with pyrolysis experiments showed that the

uracil-polystyrenes lost TEMPO in a first stage degradation from 195 to 250 ºC but that the

uracil groups remained on the polymer.

4.6 Acknowledgement

This material is based upon work supported by the U.S. Army Research Laboratory and

the U.S. Army Research Office under contract/grant number DAAD19-02-1-0275

Macromolecular Architecture for Performance (MAP) MURI.

256

Chapter 5. Supramolecular Triblock Copolymers Containing

Complementary Nucleobase Molecular Recognition

(Mather, B.D.; Baker, M.B; Beyer, F.L; Green, M.D.; Berg, M.A.G..; Long, T.E.

Macromolecules, submitted)

5.1 Abstract

A novel difunctional alkoxyamine initiator, DEPN2, was synthesized and utilized as an

efficient initiator in nitroxide-mediated controlled radical polymerization of triblock

copolymers. Complementary hydrogen bonding triblock copolymers containing adenine (A)

and thymine (T) nucleobase-functionalized outer blocks were synthesized. These

thermoplastic elastomeric block copolymers contained short nucleobase-containing outer

blocks (Mn ~ 1K-4K) and n-butyl acrylate rubber blocks of variable length (Mn ~ 14K-70K).

Hydrogen bonding interactions were observed for blends of the complementary

nucleobase-functionalized block copolymers through increased specific viscosity as well as

higher scaling exponents for specific viscosity as a function of solution concentration

compared to the individual block copolymers. In the solid state, the blends exhibited

evidence of a hard phase consisting of a mixture of complementary adenine and thymine

functional blocks, which formed upon annealing, and dynamic mechanical analysis (DMA)

revealed higher softening temperatures compared to individual block copolymers.

Morphological development of the block copolymers was studied using SAXS and AFM,

which revealed intermediate interdomain spacings and surface textures for the blends

257

compared to the individual precursors. Hydrogen bonding interactions enabled the

compatibilization of complementary hydrogen bonding guest molecules such as

9-octyladenine.

5.2 Introduction

Hydrogen bonding enables the introduction of thermoreversible properties into


Due to the reversible properties it imparts, hydrogen bonding has been studied in the context

of both supramolecular 503 and macromolecular 504 systems. The strength of these

interactions is highly dependent on temperature,505 solvent,506 humidity507 and pH,508 thus

allowing control of properties through a number of environmental parameters. The resulting

polymers often exhibit a stronger temperature dependence of melt viscosity than

non-hydrogen bonding polymers, suggesting possible advantages in melt processing.509 The

502 Yamauchi, K.; Lizotte, J. R.; Hercules, D. M.; Vergne, M. J.; Long, T. E. Combinations of Microphase

Separation and Terminal Multiple Hydrogen Bonding in Novel Macromolecules. J Am Chem Soc 2002, 124, 8599-604. 503 Brunsveld, L.; Folmer, B. J. B.; Meijer, E. W.; Sijbesma, R. P. Supramolecular Polymers. Chem Rev 2001, 101, 4071-98. 504 Ilhan, F.; Galow, T. H.; Gray, M.; Clavier, G.; Rotello, V. M. Giant Vesicle Formation through

Self-Assembly of Complementary Random Copolymers. J Am Chem Soc 2000, 122, 5895-6. 505 Lutz, J. F.; Thunemann, A. F.; Rurack, K. DNA-like “Melting” of Adenine- and

Thymine-Functionalized Synthetic Copolymers. Macromolecules 2005, 38, 8124-6. 506 Deans, R.; Ilhan, F.; Rotello, V. M. Recognition-Mediated Unfolding of a Self-Assembled Polymeric

Globule. Macromolecules 1999, 32, 4956-60. 507 Söntjens, S. H. M.; Sijbesma, R. P.; van Genderen, M. H. P.; Meijer, E. W. Stability and Lifetime of

Quadruply Hydrogen Bonded 2-Ureido-4[1H]-pyrimidinone Dimers. J Am Chem Soc 2000, 122, 7487-93. 508 Sotiropoulou, M.; Bokias, G.; Staikos, G. Soluble Hydrogen-Bonding Interpolymer Complexes and

pH-controlled Thickening Phenomena in Water. Macromolecules 2003, 36, 1349-54. 509 Yamauchi, K.; Kanomata, A.; Inoue, T.; Long, T. E. Thermoreversible Polyesters Consisting of

Multiple Hydrogen Bonding (MHB). Macromolecules 2004, 37, 3519-22.

258

strength of hydrogen bonding associations is further tunable via structural and geometric

parameters as well as molecular design of the hydrogen bonding sites.510511512

- 513 Association

strengths range from 102 M-1 for DNA nucleobases, 514 to self-complementary

ureidopyrimidone (UPy) hydrogen bonding groups,515 which possess association constants

on the order of 107 M-1.

Sivakova and Rowan recently reviewed the use of nucleobases in supramolecular

assembly and hydrogen bonding polymers.516 Rowan et al. noted that the behavior of the

isolated nucleobases in synthetic polymers is quite different from their behavior in DNA

where they are bound to a complementary base.517 Multiple complementary association

modes are possible for nucleobases, including the classical Watson-Crick mode516 which is

present in DNA as well as the less commonly observed Hoogsteen association mode.518

510 Beijer, F. H.; Sijbesma, R. P.; Kooijman, H.; Spek, A. L.; Meijer, E. W. Strong Dimerization of

Ureidopyrimidones via Quadruple Hydrogen Bonding. J Am Chem Soc 1998, 120, 6761-9. 511 Beijer, F. H.; Sijbesma, R. P. V., J.A.J.M.; Meijer, E. W. K., H.; Spek, A.L. Hydrogen-Bonded Complexes of Diaminopyridines and Diaminotriazines: Opposite Effect of Acylation on Complex Stabilities. J. Org. Chem. 1996, 61, 6371-80. 512 Jorgensen, W. L.; Pranata, J. Importance of Secondary Interactions in Triply Hydrogen Bonded

Complexes: Guanine-Cytosine vs Uracil-2,6-Diaminopyridine. J Am Chem Soc 1990, 112, 2008-10. 513 Pranata, J.; Wierschke, S. G.; Jorgensen, W. L. OPLS potential functions for nucleotide bases. Relative

association constants of hydrogen-bonded base pairs in chloroform. J Am Chem Soc 1991, 113, 2810-9. 514 Kyogoku, Y.; Lord, R. C.; Rich, A. The Effect of Substituents on the Hydrogen Bonding of Adenine

and Uracil Derivatives. Proc Natl Acad Sci USA 1967, 57, 250-7. 515 Brunsveld, L.; Folmer, B. J. B.; Meijer, E. W.; Sijbesma, R. P. Supramolecular Polymers. Chem Rev 2001, 101, 4071-98. 516 Sivakova, S.; Rowan, S. J. Nucleobases as supramolecular motifs. Chem Soc Rev 2005, 34, 9-21. 517 Sivakova, S.; Bohnsak, D. A.; Mackay, M. E.; Suwanmala, P.; Rowan, S. J. Utilization of a

Combination of Weak Hydrogen-Bonding Interactions and Phase Segregation to Yield Highly

Thermosensitive Supramolecular Polymers. J Am Chem Soc 2005, 127, 18202-11. 518 Ghosal, G.; Muniyappa, K. Hoogsteen base-pairing revisited: Resolving a role in normal biological

processes and human diseases. Biochemical and Biophysical Research Communications 2006, 343, 1-7.

259

Furthermore, nucleobases exhibit several weak self-association modes (Ka < 10 M-1),514

which compete with the complementary association modes.

Hydrogen bonding block copolymers differ from randomly functionalized copolymers

since the placement of the hydrogen bonding groups is localized to a specific region of the

polymer backbone. This leads to a dramatic difference in morphology and physical

properties due to a potential synergy between microphase separation and hydrogen bonding

interactions. Multiplicative and cooperative effects of the neighboring hydrogen bonding

groups lead to stronger associations519,520 which reinforce microphase separation. Specific

hydrogen bonding can increase the tendency of block copolymers to microphase separate

through strong associations between chains. Therefore, only short hydrogen bonding blocks

are necessary to achieve microphase separation.521 In some cases, microphase separation

can occur even for a single hydrogen bonding group at the chain ends (i.e. telechelic

functionality). 522 Others have noted the synergy between microphase separation and

hydrogen bonding.523 Nowick et al. also observed enhanced hydrogen bonding interactions

519 Pan, J.; Chen, M.; Warner, W.; He, M.; Dalton, L.; Hogen-Esch, T. E. Synthesis and Self-Assembly of Diblock Copolymers through Hydrogen Bonding. Semiquantitative Determination of Binding Constants. Macromolecules 2000, 33, 7835-41. 520 Kriz, J.; Dybal, J.; Brus, J. Cooperative Hydrogen Bonds of Macromolecules. 2. Two-Dimensional Cooperativity in the Binding of Poly(4-vinylpyridine) to Poly(4-vinylphenol). J Phys Chem B 2006, 110, 18338-46. 521 Leibler, L. Theory of Microphase Separation in Block Copolymers. Macromolecules 1980, 13, 1602-17. 522 Sivakova, S.; Bohnsak, D. A.; Mackay, M. E.; Suwanmala, P.; Rowan, S. J. Utilization of a Combination of Weak Hydrogen-Bonding Interactions and Phase Segregation to Yield Highly Thermosensitive Supramolecular Polymers. J Am Chem Soc 2005, 127, 18202-11. 523 Brunsveld, L.; Folmer, B. J. B.; Meijer, E. W.; Sijbesma, R. P. Supramolecular Polymers. Chem Rev 2001, 101, 4071-98.

260

through localization of nucleobases in sodium dodecyl sulfate micellar cores in aqueous

media.524

Others have previously synthesized nucleobase-containing block copolymers via living

polymerization techniques such as atom transfer radical polymerization (ATRP)525526527

-528529

530 and

ring opening methathesis polymerization (ROMP).531 , 532 Van Hest et al. synthesized

thymine-functionalized block copolymers via ATRP of a thymine methacrylate monomer

from a PEG-macroinitiator. 533 Thymine-containing, cinnamate-functionalized

photocrosslinkable block copolymers were synthesized via ATRP.526 -530 Hydrogen bonding

interactions facilitated association of guest molecules into the core of micelles which were

formed in selective solvents. The micelles were then photocrosslinked and the hydrogen

bonding guest molecules were extracted, resulting in hollow nanospheres for potential drug

524 Nowick, J. S.; Chen, J. S.; Noronha, G. Molecular recognition in micelles: the roles of hydrogen bonding and hydrophobicity in adenine-thymine base-pairing in SDS micelles. J Am Chem Soc 1993, 115, 7636-44. 525 Spijker, H. J.; Dirks, A. J.; van Hest, J. C. M. Unusual rate enhancement in the thymine assisted ATRP process of adenine monomers. Polymer 2005, 46, 8528-35. 526 Zhou, J.; Li, Z.; Liu, G. Diblock Copolymer Nanospheres with Porous Cores. Macromolecules 2002, 35, 3690-6. 527 Liu, G.; Zhou, J. First- and Zero-Order Kinetics of Porogen Release from the Cross-Linked Cores of Diblock Nanospheres. Macromolecules 2003, 36, 5279-84. 528 Hu, J.; Lui, G. Chain Mixing and Segregation in B-C and C-D Diblock Copolymer Micelles. Macromolecules 2005, 38, 8058-65. 529 Yan, X.; Liu, G.; Hu, J.; Willson, C. G. Coaggregation of B-C and D-C Diblock Copolymers with H-Bonding C Blocks in Block-Selective Solvents. Macromolecules 2006, 39, 1906-12. 530 Li, Z.; Ding, J.; Day, M.; Tao, Y. Molecularly Imprinted Polymeric Nanospheres by Diblock Copolymer Self-Assembly. Macromolecules 2006, 39, 2629-36. 531 Bazzi, H.; Sleiman, H. Adenine-Containing Block Copolymers via Ring-Opening Metathesis Polymerization: Synthesis and Self-Assembly into Rod Morphologies. Macromolecules 2002, 35, 9617-20. 532 Nair, K. P.; Pollino, J. M.; Weck, M. Noncovalently Functionalized Block Copolymers Possessing Both Hydrogen Bonding and Metal Coordination Centers. Macromolecules 2006, 39, 931-40. 533 Spijker, H. J.; Dirks, A. J.; van Hest, J. C. M. Unusual rate enhancement in the thymine assisted ATRP process of adenine monomers. Polymer 2005, 46, 8528-35.

261

delivery applications. Sleiman et al. have synthesized adenine-functionalized block

copolymers through ROMP of substituted oxonorbornene monomers, and subsequently

formed cylindrical-shaped structures during evaporation from dilute solution.531 Weck et al.

recently demonstrated the combination of nucleobase hydrogen bonding and metal-ligand

coordination interactions in block copolymers synthesized via ROMP.534 Matsushita et al.

have also synthesized nucleoside-containing block copolymers using stepwise

phosphoramidite coupling techniques.535 Significant effort was also devoted to studying

nucleobase-containing homopolymers and random polymers.536537538

-539540541

542

Nitroxide mediated polymerization (NMP) is a well established controlled radical

polymerization methodology which enables block copolymer synthesis with a wide range of

acrylic and styrenic monomers. 543 Controlled radical polymerization techniques are

534 Nair, K. P.; Pollino, J. M.; Weck, M. Noncovalently Functionalized Block Copolymers Possessing Both Hydrogen Bonding and Metal Coordination Centers. Macromolecules 2006, 39, 931-40. 535 Noro, A.; Nagata, Y.; Tsukamoto, M.; Hayakawa, Y.; Takano, A.; Matsushita, Y. Novel Synthesis and Characterization of Bioconjugate Block Copolymers Having Oligonucleotides. Biomacromolecules 2005, 6, 2328-33. 536 Ilhan, F.; Galow, T. H.; Gray, M.; Clavier, G.; Rotello, V. M. Giant Vesicle Formation through Self-Assembly of Complementary Random Copolymers. J Am Chem Soc 2000, 122, 5895-6. 537 Lutz, J. F.; Thunemann, A. F.; Rurack, K. DNA-like “Melting” of Adenine- and Thymine-Functionalized Synthetic Copolymers. Macromolecules 2005, 38, 8124-6. 538 Marsh, A.; Khan, A.; Haddleton, D. H.; Hannon, M. J. Atom Transfer Polymerization: Use of Uridine and Adenosine Derivatized Monomers and Initiators. Macromolecules 1999, 32, 8725-31. 539 Lutz, J. F.; Thunemann, A. F.; Nehring, R. Preparation by Controlled Radical Polymerization and Self-Assembly via Base-Recognition of Synthetic Polymers Bearing Complementary Nucleobases. J Polym Sci, Part A: Polym Chem 2005, 43, 4805-18. 540 Puskas, J. E.; Dahman, Y.; Margaritas, A.; Cunningham, M. F. Novel Thymine-Functionalized Polystyrenes for Applications in Biotechnology. 2. Adsorption of Model Proteins. Biomacromolecules 2004, 5, 1412-21. 541 Brahme, N. M.; Smith, W. T. Synthesis of Some Graft Copolymers of Uracil. J Polym Sci, Part A: Polym Chem 1984, 22, 813-20. 542 Kaye, H. Cyclopolymerization of N-Vinyluracil. Macromolecules 1971, 4, 147-52. 543 Hawker, C. J.; Bosman, A. W.; Harth, E. New Polymer Synthesis by Nitroxide Mediated Living Radical Polymerizations. Chem. Rev. 2001, 101, 3661-88.

262

particularly suited for the hydrogen bonding block copolymers, due to tolerance for protic

functionality543 and absence of residual catalyst metals, which were demonstrated to

coordinate to nucleobases and affect polymerization kinetics. 544 Despite the many

advantages of nitroxide-mediated polymerization, only one brief report exists in the prior

literature regarding synthesis of nucleobase-functionalized block copolymers using NMP.545

In the present work, N-tert-butyl-N-(1-diethylphosphono-2,2-dimethylpropyl)-N-oxyl (DEPN,

Scheme 1) nitroxide is utilized, which was developed earlier by Gnanou and Tordo, and is

capable of mediating the polymerization of acrylic monomers.546 In order to achieve

symmetric triblock copolymers in two synthetic steps, a novel difunctional alkoxyamine

initiator (DEPN2, Figure 5.1) was utilized in the present polymerizations. The use of

difunctional initiation is further advantageous due to the difficulties in crossover from

styrenic to acrylic monomers that are observed in nitroxide mediated polymerization.547

Furthermore, alkoxyamine initiators facilitate controlled molecular weights due to the 1:1

stoichiometry between the initiating fragment and the nitroxide and allow chain-end

functionality as reported earlier in our laboratories.548,549

544 Spijker, H. J.; Dirks, A. J.; van Hest, J. C. M. Unusual rate enhancement in the thymine assisted ATRP process of adenine monomers. Polymer 2005, 46, 8528-35. 545 Saito, K.; Ingalls, L.; Warner, J. C. Core-Bound Nanomicelles Base on Hydrogen Bonding and Photocrosslinking of Thymine Polym Prep 2006, 47, 829-30. 546 Grimaldi, S.; Finet, J. P.; Le Moigne, F.; Zeghdaoui, A.; Tordo, P.; Benoit, D.; Fontanille, M.; Gnanou, Y. Acyclic β-Phosphonylated Nitroxides: A New Series of Counter-Radicals for "Living"/Controlled Free Radical Polymerization. Macromolecules 2000, 33, 1141-7. 547 Robin, S.; Gnanou, Y. Triblock copolymers based on styrene and n-butyl acrylate by nitroxide-mediated radical polymerization: problems and solutions. . Macromolecular Symposia 2001, 165, 43-53. 548 Mather, B. D.; Lizotte, J. R.; Long, T. E. Synthesis of Chain End Functionalized Multiple Hydrogen Bonded Polystyrenes and Poly(alkyl acrylates) Using Controlled Radical Polymerization. Macromolecules 2004, 37, 9331-7.

263

In this manuscript, we discuss combinations of nitroxide-mediated radical

polymerization with complementary adenine (A) and thymine (T) nucleobase hydrogen

bonding in block copolymer architectures (Figure 5.1). Furthermore, we examine the

effects of hydrogen bonding in blends of complementary nucleobase-functionalized block

copolymers. Due to the atactic polymer backbone in the present work, a well-ordered

double helical complex is not predicted as suggested from the structure of DNA. Instead,

associated structures are more likely to consist of multiple polymer chains with one or more

associated A-T nucleobase pairs. Future work will involve substitution on tactic polymers

to ascertain the effects of tacticity on organization of the intermolecular association.

549 Robin, S.; Guerret, O.; Couturier, J. L.; Pirri, R.; Gnanou, Y. Synthesis and Characterization of Poly(styrene-b-n-butyl acrylate-b-styrene) Triblock Copolymers Using a Dialkoxyamine as Initiator. Macromolecules 2002, 35, 3844-8.

264

Figure 5.1. Synthesis of adenine and thymine nucleobase-functionalized triblock

copolymers.(a) Pictorial representation of hydrogen bonding association of complementary

adenine and thymine block copolymers in polymer blends.(b)

a)

b)

N

N

N

NN

N

O N O

CH3

H

HHN

N

N

NN

H

H

N

O N O

CH3

H

EtO

OEtO

O

DEPNDEPN

EtO

OEtO

O

OBuO

O OBu

n nn n

1) n-butyl acrylate

2)

NN N

N NR =

N

ON

O

CH3

adenine (A) thymine (T)

H

H

H

or

DEPNDEPN

NO

PO

OEtOEt

DEPN =

DEPN2R

R

R

265

5.3 Experimental

5.3.1 Materials

n-Butyl acrylate (99%) was purchased from Aldrich and purified using an alumina

column and subsequent vacuum distillation from calcium hydride.

Diethyl-meso-2,5-dibromoadipate (98%), copper (I) bromide (99.999%),

N,N,N’,N”,N”-pentamethyldiethylenetriamine (PMDETA) (98%) and

N,N-dimethylformamide (DMF, anhydrous, 99.8%) were purchased from Aldrich and used

without further purification. Copper powder (45 μm, 99%) was purchased from Acros and

used as received. DEPN, 550 Styryl-DEPN, 551 1-vinylbenzyl thymine, 552 9-vinylbenzyl

adenine,553 and 9-octyladenine554 were synthesized according to the previous literature.

5.3.2 Synthesis of DEPN2

DEPN (2.0 g, 6.8 mmol) and diethyl-meso-2,5-dibromoadipate (1.36 g, 3.8 mmol) were

charged to a one-necked 100-mL round-bottomed flask containing a magnetic stirbar. CH2Cl2

(30 mL) was added and the solution was degassed with three freeze-pump-thaw cycles. In a

550 Grimaldi, S.; Finet, J. P.; Le Moigne, F.; Zeghdaoui, A.; Tordo, P.; Benoit, D.; Fontanille, M.; Gnanou, Y. Acyclic β-Phosphonylated Nitroxides: A New Series of Counter-Radicals for "Living"/Controlled Free Radical Polymerization. Macromolecules 2000, 33, 1141-7. 551 Diaz, T.; Fischer, A.; Jonquieres, A.; Brembilla, A.; Lochon, P. Controlled Polymerization of Functional Monomers and Synthesis of Block Copolymers Using a β-Phosphonylated Nitroxide. Macromolecules 2003, 36, 2235-41. 552 Sedlak, M.; Simunek, P.; Antonietti, M. Synthesis and 15 NMR Characterization of 4-Vinylbenzyl Substituted Bases of Nucleic Acids. J Heterocyclic Chem 2003, 40, 671-75. 553 Srivatsan, S. G.; Parvez, M.; Verma, S. Modeling of Prebiotic Catalysis with Adenylated Polymeric Templates: Crystal Structure Studies and Kinetic Characterization of Template-Assisted Phosphate Ester Hydrolysis. Chem. Eur. J. 2002, 8, 5184-91. 554 Bunton, C. A.; Wolfe, B. B. Acid and micellar catalysis of the decomposition of 9-alkylpurine-6-diazotates. J Am Chem Soc 1974, 96, 7747-52.

266

second 100-mL round-bottomed flask, PMDETA (2.34 g, 13.6 mmol) was dissolved in 20 mL

CH2Cl2 and subjected to the same degassing. In a third 100-mL round-bottomed flask

containing a stirbar, CuBr (0.78 g, 5.47 mmol) and Cu powder (0.35 g, 5.47 mmol) were

purged with nitrogen gas. After degassing, the liquid reagents were transferred using a

cannula into the flask containing the copper powder and CuBr. The reaction was stirred at 25

oC for 24 h, diluted with CH2Cl2 (200 mL), and washed repeatedly with water (10 x 100 mL),

to remove copper compounds. The organic layer was then dried over sodium sulfate and

evaporated. The product was separated on silica, eluting with ethyl acetate : hexane (1:1). The

difunctional alkoxyamine initiator based on DEPN nitroxide (DEPN2, as shown in Scheme 1)

was isolated as a mixture of diastereomers. FAB MS: m/z = 789.4842 [M+H]+ experimental,

m/z = 789.48 theoretical. A peak for the monofunctional product was not observed (m/z =

574.5). 1H NMR (400 MHz, CDCl3, 25 °C) (δ, ppm): 1.0-1.2 ppm (s, tBu, 36H), 1.2-1.4 ppm

(m, ester CH3, 18H), 1.6-2.4 ppm (br s, linker CH2, 4H), 3.1-3.6 ppm (m, DEPN CH, 2H),

3.9-4.2 ppm (m, CH3, 12H), 4.4-4.5 ppm (m, COCH, 2H). 13C NMR (101 MHz, CDCl3, 25

°C) (δ, ppm): 13.90, 13.98, 14.03, 16.08, 16.14, 16.32, 16.35, 16.41, 16.47, 26.46, 26.52,

26.67, 26.96, 27.53, 27.56, 27.89, 27.95, 28.12, 29.38, 29.44, 29.89, 29.93, 30.12, 30.18,

34.48, 35.09, 35.16, 35.21, 35.49, 35.58, 35.64, 58.82, 58.89, 60.22, 60.27, 60.32, 60.40,

60.62, 61.57, 61.66, 61.96, 62.03, 62.23, 62.30, 68.62, 68.90, 69.99, 70.27, 75.31, 76.85,

77.20, 81.52, 81.87, 86.31, 86.74, 171.46, 172.74, 31P NMR (162 MHz, CDCl3, 25 °C) (δ,

ppm): 24.91, 25.00, 25.20, 25.59, 25.63, 25.82.

Meso diastereomer of DEPN2: The meso diastereomer was isolated from the partly

crystalline fractions, which eluted first during chromatographic purification of DEPN2.

267

Further separation was achieved via triturating the semicrystalline mixture with hexane. m.p.

= 139.5-141.5 °C. 1H NMR (400 MHz, CDCl3, 25 °C) (δ, ppm): 1.03 (s, N-tBu, 18H), 1.06 (s,

C-tBu, 18H), 1.24 (m, ester CH3, 18H), 1.55-2.40 (br, linker CH2, 4H), 3.18 (d, J = 25 Hz,

DEPN CH, 2H), 3.85-4.20 (m, OCH2, 12H), 4.25-4.46 (br, OCH, 2H). 13C NMR (101 MHz,

CDCl3, 25 °C) (δ, ppm): 13.95, 16.31 (dd, J1 = 28.4 Hz, J2 = 6.2 Hz), 27.94, 28.57, 29.31 (d, J

= 6.2 Hz), 35.59 (d, J = 5.4 Hz), 58.69 (d, J = 7 Hz), 61.05 (d, J = 95 Hz), 61.80 (d, J = 6.1

Hz), 69.71 (d, J = 138 Hz), 86.65, 172.89. 31P NMR (162 MHz, CDCl3, 25 °C) (δ, ppm):

25.67.

5.3.3 Polymerization of n-Butyl Acrylate with DEPN2

DEPN2 (106 mg, 0.134 mmol) and DEPN (17 mg, 0.057 mmol) were weighed into a

100-mL round-bottomed flask containing a magnetic stirbar. The flask was sealed with a

three-way joint allowing introduction of reagents via syringe, application of vacuum, and

nitrogen. The flask was evacuated to 60 mtorr and refilled with high-purity nitrogen three

times. Purified n-butyl acrylate (25 mL, 174 mmol) was added and the mixture was degassed

with three freeze-pump-thaw cycles. Finally, the flask was immersed in an oil bath

thermostated at 130 oC for 75 min. After the polymerization, residual monomer was removed

in vacuo (60 mtorr, 40 oC, 6 h). SEC analysis in THF revealed molecular weight data Mn =

23,700, Mw/Mn = 1.11.

5.3.4 Synthesis of Thymine-Containing Block Copolymer

Poly(n-butyl acrylate) homopolymer (208 mg, Mn = 23,700) and 1-vinylbenzylthymine

268

(56 mg, 0.23 mmol) were added to a 50-mL round-bottomed flask with a magnetic stirbar.

The flask was sealed with a three-way joint and evacuated to 60 mtorr and refilled with

high-purity nitrogen three times. DMF (2 mL) was then syringed into the flask and the

mixture was degassed with three freeze-pump-thaw cycles. The flask was then immersed in

an oil bath at 120 oC for 2 h. After the polymerization, the polymer was isolated via

precipitation into methanol. 1H NMR spectroscopy (CDCl3 + DMSO-d6) revealed block

molecular weights T2.0K-nBA23.7K-T2.0K. 1H NMR (400 MHz, CDCl3 + DMSO-d6 (1:1 w/w),

25 °C) (δ, ppm): 0.86 (t, CH3, 3H) 1.29 (q, COOCH2CH2CH2CH3, 2H), 1.5 (br,

CH2-CH-COO and COOCH2CH2-), 1.7 (br, CH2-CH-COO-, 1H), 2.1 (br, CH-COO-, 1H) ,

3.9 (br, COOCH2, 2H) , 4.7 (br, Ph-CH2, 2H), 6.3 (br, Ph, 2H), 6.9 (br, Ph, 2H), 7.2 (br s,

N-C=CH, 1H), 11.0 (s, NH, 1H).

5.3.5 Synthesis of Adenine-Containing Block Copolymer

Poly(n-butyl acrylate) homopolymer (170 mg, Mn = 23,700) and 9-vinylbenzyladenine

(77 mg, 0.31 mmol) were added to a 50-mL round-bottomed flask with a magnetic stirbar.

The flask was sealed with a three-way joint and evacuated to 60 mtorr and refilled with

high-purity nitrogen three times. DMF (1 mL) was then syringed into the flask and the

mixture was degassed with three freeze-pump-thaw cycles. The flask was then immersed in

an oil bath at 120 oC for 2 h. After the polymerization, the polymer was isolated via

precipitation into methanol. 1H NMR spectroscopy revealed block molecular weights

A2.8K-nBA23.7K-A2.8K. 1H NMR (400 MHz, DMSO-d6, 25 °C) (δ, ppm): 0.86 (t, CH3, 3H) 1.30

(q, COOCH2CH2CH2CH3, 2H), 1.5 (br, CH2-CH-COO and COOCH2CH2-), 1.75 (br,

269

CH2-CH-COO-, 1H), 2.2 (br, CH-COO-, 1H), 4.0 (br, COOCH2, 2H), 5.2 (br, Ph-CH2, 2H),

6.3 (br, Ph, 2H), 6.9 (br, Ph, 2H), 7.6 (br, NH2, 2H), 8.1 (br, adenine ring protons, 2H).

5.3.6 Blends of Adenine and Thymine Functionalized Block Copolymers and Sample

Preparation

An example of solution blending is provided for the A1 and T1 pair. Adenine containing

block copolymer A1.5K-nBA15.9K-A1.5K (0.300 g, 0.19 mmol A) and thymine containing block

copolymer T1.8K-nBA13.9K-T1.8K (0.216 g, 0.19 mmol T) were weighed into a vial containing a

magnetic stirbar and chloroform (10 mL) was added. The vial was sealed and stirred for 18 h

until the solid polymer was no longer visible. Films were cast in PTFE molds from solution

and dried in a vacuum oven at 40 oC, with subsequent storage in a dessicator. Films were

annealed at 155 oC under vacuum or 200 oC under nitrogen for 18 h.

For DMA and SAXS, polymer samples were cast from chloroform in PTFE molds and

were dried under vacuum at 40 oC, with subsequent storage in a dessicator. In some cases

(A1, T1, A1/T1), melt pressing (160 oC, 5 min) between PTFE films was necessary to obtain

uniform films. Subsequent annealing steps were performed at 155 oC under vacuum for 18 h

or at 135 oC under vacuum for A3, T3, A3/T3. In some cases, annealing at 200 oC for 18 h

was performed under nitrogen.

For AFM studies, polymer films were solution cast from chloroform (~0.5 wt%

polymer) on silicon wafers at 3000 rpm, which resulted in thickness values near 100 nm.

Prior cleaning of the silicon wafers consisted of rinsing with chloroform and drying under a

high pressure nitrogen stream. Annealing of the AFM film samples was conducted at 155 oC

270

under vacuum or 200 oC under nitrogen for 18 h.


In-situ FTIR spectroscopic analysis was performed using a Mettler-Toledo ReactIR

1000 attenuated total reflectance (ATR) spectrometer equipped with a diamond composite

(DiComp™) probe.55555647, 48 Reaction kinetics were determined through the measuring the

consumption of n-butyl acrylate, which was monitored with the disappearance of the acrylate

absorbance at 968 cm-1. Size exclusion chromatography (SEC) was performed at 40 °C in

HPLC grade THF at 1 mL/min using a Waters size-exclusion chromatographer equipped with

an autosampler, 3 in-line 5 μm PLgel MIXED-C columns. Detectors included a Waters 410

differential refractive index (DRI) detector operating at 880 nm, and a Wyatt Technologies

miniDAWN multiangle 690 nm laser light scattering (MALLS) detector, calibrated with PS

standards. All reported molecular weight values are absolute molecular weights obtained

using the MALLS detector. 1H NMR spectroscopic data was collected in CDCl3 or mixtures

of CDCl3 and DMSO-d6 and (2:1) on a Varian 400 MHz spectrometer at 25 oC. FAB MS was

conducted in positive ion mode on a JEOL HX110 Dual Focusing Mass Spectrometer using

xenon ion bombardment, polyethylene glycol (PEG) standards and a 3-nitrobenzyl alcohol

matrix.

DMA was conducted in film tension mode on 9.5 mm x 6.0 mm x 0.6 mm (l x w x t)

rectangular strips on a TA Instruments Q800 DMA at a 3 oC/min scan rate, 1 Hz frequency.

555 Pasquale, A. J.; Lizotte, J. R.; Williamson, D. T.; Long, T. E. The allure of "molecular videos": In-situ infrared spectroscopy of polymerization processes. Polym News 2002, 27, 272-83. 556 Lizotte, J. R.; Long, T. E. Stable Free-Radical Polymerization of Styrene in Combination with 2-Vinylnaphthalene Initiation Macromol Chem Phys 2003, 204, 570-6.

271

Solution rheology measurements were conducted on a TA Instruments G2 Rheometer in

concentric cylinder geometry in chloroform. Melt rheology was performed using a TA

Instruments AR2000 rheometer at 1 Hz frequency and 2.5 % strain at 160 oC.

A Veeco MultiMode™ scanning probe microscope was used for tapping-mode AFM

imaging. Samples were imaged at a set-point ratio of 0.6 at magnifications of 500 nm x 500

nm. Veeco’s Nanosensor silicon tips having spring constants of 10-130 N/m were utilized for

imaging.

For SAXS, CuKα X-ray radiation was generated using a Rigaku Ultrax18 rotating anode

X-ray generator operated at 45 kV and 100 mA. A nickel filter was used to eliminate all

wavelengths but the CuKα doublet, with an average wavelength of λ = 1.542 Å. The exact

beam center and the sample-to-detector distance of approximately 1.5 m were calibrated

using silver behenate.557 The 3 m camera uses 3-pinhole collimation (300, 200 and 600 μm),

and a sample-to-detector distance of approximately 1.5 m. Two-dimensional data sets were

collected using a Molecular Metrology 2D multi-wire area detector. The data were

corrected for detector noise, sample absorption, and background scattering, followed using

azimuthal averaging to obtain intensity as a function of the scattering vector, I(q), where q =

4π·sin(θ)/λ and 2θ is the scattering angle. The data were then placed on an absolute scale

using a 1.07 mm thick type 2 glassy carbon sample, previously calibrated at the Advanced

Photon Source in the Argonne National Laboratory, as a secondary standard. All data

processing and analysis were done using Wavemetrics IGOR Pro 5.04 software and IGOR

procedures written by Dr. Jan Ilavsky of Argonne National Laboratory.

557 Huang, T. C.; Toraya, H.; Blanton, T. N.; Wu, Y. X-ray powder diffraction analysis of silver behenate, a possible low-angle diffraction standard. J Appl Cryst 1993, 26, 180-4.

272


5.4.1 Synthesis of a Novel Difunctional Alkoxyamine Initiator

A novel, difunctional alkoxyamine initiator based on DEPN, (DEPN2), was synthesized

via conventional copper-promoted atom transfer radical addition techniques from a

commercially available dihalide precursor (Figure 1).558 DEPN2 contains four chiral centers,

which leads to the existence of 16 diastereomers, and typically an oily product. The chemical

structure of DEPN2 was confirmed via 1H, 13C and 31P NMR spectroscopies as well as fast

atom bombardment (FAB) mass spectrometry, however, the presence of multiple

diastereomers complicated the spectral assignments. A meso diastereomer of DEPN2 (Figure

5.2) was isolated via chromatography in a crystalline form, and this was subjected to X-ray

crystallography,559 conclusively confirming the identity of the initiator. Unlike previously

described difunctional alkoxyamine initiators,560 DEPN2 possesses a non-hydrolyzable linker

in the main chain, which provides protection against hydrolytic degradation of the final

polymer.

558 Matyjaszewski, K.; Woodworth, B. E.; Zhang, X.; Gaynor, S.; Metzner, Z. Simple and Efficient Synthesis of Various Alkoxyamines for Stable Free Radical Polymerization. Macromolecules 1998, 31, 5955-7. 559 Mather, B. D. Baker, M.B.; Beyer, F.L.; Green, M.D.; Berg, M.A.G.; Long, T.E. Multiple Hydrogen Bonding for the Reversible Attachment of Ionic Functionality in Block Copolymers. Macromolecules 2007, submitted. 560 Robin, S.; Guerret, O.; Couturier, J. L.; Pirri, R.; Gnanou, Y. Synthesis and Characterization of Poly(styrene-b-n-butyl acrylate-b-styrene) Triblock Copolymers Using a Dialkoxyamine as Initiator. Macromolecules 2002, 35, 3844-8.

273

H

H

R

S

ONt-Bu

P

t-Bu

O

OEtOEt

H

S

EtOO

ON t-Bu

P

t-Bu

O

EtOEtO

H

R

OEtO

Figure 5.2. Synthesis of DEPN2, difunctional alkoxyamine initiator, using copper-promoted

reaction of an activated dihalide. (a) Crystalline meso diastereomer of DEPN2. (b)

EtO

O

O

OEt

Br

Br

EtO

O

O

OEt

O

O2 DEPN

CuBr / Cuo

PMDETACH2Cl2

NP

O

EtOEtO

NP

O

OEtOEt

"DEPN2"

a) b)

274

5.4.2 Performance of DEPN2 in the Homopolymerization of n-Butyl Acrylate

The target nucleobase-containing block copolymers possess hydrogen bonding styrenic

outer blocks and a rubbery poly(n-butyl acrylate) central block (Figure 5.1). Thus, initial

studies focused on evaluating the performance of DEPN2 in n-butyl acrylate polymerization.

Poly(n-butyl acrylate) offers a low glass transition temperature, which provides a wide

service window for block copolymers (Tg = -40 oC).561 Additional DEPN (0.4 equiv.) was

added to maintain control of the n-butyl acrylate polymerizations, which was shown

previously to be necessary in the polymerization of acrylic monomers.562

In order to probe the performance of DEPN2 in the homopolymerization of n-butyl

acrylate, kinetic studies were coupled with absolute molecular weight determination using

SEC analysis. In-situ FTIR, which is a useful technique for monitoring reactions in

real-time,563 was employed to study the kinetics of the n-butyl acrylate homopolymerization

through monitoring the disappearance of the acrylate absorbance at 968 cm-1 as previously

reported.564 The DEPN2 initiated polymerizations of n-butyl acrylate exhibited pseudo

first-order kinetics, which was consistent with a controlled radical polymerization. SEC

analysis of fractions that were removed from the reaction produced a linear molecular weight

(Mn) versus conversion profile, which indicated a constant number of propagating chain ends

that is consistent with a living polymerization process (Figure 5.3). Furthermore, SEC traces

561 Brandrup, J.; Immergut, E. H., Polymer Handbook. 3rd ed.; Wiley: New York, 1989. 562 Lacroix-Desmazes, P.; Lutz, J. F.; Chauvin, F.; Severac, R.; Boutevin, B. Living Radical Polymerization: Use of an Excess of Nitroxide as a Rate Moderator. Macromolecules 2001, 34, 8866-71. 563 Pasquale, A. J.; Lizotte, J. R.; Williamson, D. T.; Long, T. E. Polym News 2002, 27, 272-83. 564 Mather, B. D.; Lizotte, J. R.; Long, T. E. Synthesis of Chain End Functionalized Multiple Hydrogen Bonded Polystyrenes and Poly(alkyl acrylates) Using Controlled Radical Polymerization. Macromolecules 2004, 37, 9331-7.

275

were unimodal with narrow polydispersities (Mw/Mn ~ 1.10), providing additional evidence

for controlled radical polymerization.

276

Minutes15.00 16.00 17.00 18.00 19.00 20.00 21.00 22.00 23.00 24.00 25.00

time

Minutes15.00 16.00 17.00 18.00 19.00 20.00 21.00 22.00 23.00 24.00 25.00

Minutes15.00 16.00 17.00 18.00 19.00 20.00 21.00 22.00 23.00 24.00 25.00

time

0

10000

20000

30000

40000

50000

60000

0 5 10 15 20

Conversion (%)

Mn

(g/m

ol)

In situ FTIR1H NMR

Figure 5.3. SEC analysis of polymerization with time of n-butyl acrylate from DEPN2 and

linear molecular weight versus conversion plot.

277

Once the control of n-butyl acrylate polymerization with DEPN2 was established, it was

necessary to demonstrate the difunctional nature of DEPN2, which is essential to the synthesis

of well-defined triblock copolymers. This was accomplished using a technique that was

developed in the earlier literature, whereby n-butyl acrylate polymerizations were conducted

with initiator mixtures of DEPN2 and a monofunctional alkoxyamine initiator Sty-DEPN.565

Assuming equal propagation rates for Sty-DEPN and the two initiating sites of DEPN2, the

molecular weight of the polymer formed with DEPN2 should be higher (doubled compared to

the Sty-DEPN initiated polymers). As shown in Figure 5.4, the SEC analysis of these

polymers exhibited a bimodal molecular weight distribution with a 2:1 molecular weight ratio

of the two peaks, which confirmed our assumption and the difunctional nature of DEPN2.

565 Diaz, T.; Fischer, A.; Jonquieres, A.; Brembilla, A.; Lochon, P. Controlled Polymerization of Functional Monomers and Synthesis of Block Copolymers Using a β-Phosphonylated Nitroxide. Macromolecules 2003, 36, 2235-41.

278

Minutes15.00 17.00 19.00 21.00 23.00 25.00

Mp = 50000Mp = 24500

Minutes15.00 17.00 19.00 21.00 23.00 25.00

Mp = 50000Mp = 24500

Figure 5.4. SEC trace from a polymerization containing DEPN2 (difunctional) and Sty-DEPN

(monofunctional) initiators.

Sty-DEPN

ON P

O

OO

DEPN2

EtO

O

O

OEt

O

O

NP

O

EtOEtO

NP

O

OEtOEt

279

5.4.3 Synthesis of Nucleobase-Functionalized Hydrogen Bonding Block Copolymers

Initial efforts in the synthesis of block copolymers using DEPN2 focused on optimizing

the conditions for the synthesis of non-hydrogen bonding poly(styrene-b-n-butyl

acrylate-b-styrene) triblock copolymers. Block copolymerization, which was performed in a

similar fashion to literature procedures,566 was conducted in the absence of solvent at 120 oC

without additional DEPN for the preparation of poly(styrene-b-n-butyl acrylate-b-styrene)

triblock copolymers. Copolymerization reactions resulted in low polydispersities (Mw/Mn =

1.17) and unimodal SEC traces for a range of styrene block molecular weights (15K to 26K).

Furthermore, optically clear, elastic block copolymer films were formed from solution

casting, and AFM imaging revealed microphase separated surface morphologies.

Nucleobase-functionalized block copolymers were synthesized using analogous

conditions to those for the synthesis of styrenic triblock copolymers. Adenine and thymine

hydrogen bonding groups were introduced via nucleobase-containing styrenic monomers,

1-vinylbenzylthymine and 9-vinylbenzyladenine (Figure 5.1). In contrast to the bulk

polymerizations of non-functional styrenic block copolymers, solvent (DMF) was employed

to dissolve the solid nucleobase-containing monomers, which resulted in homogeneous

polymerizations. Purified polymer products were obtained through precipitation into

methanol, which removed residual monomers and solvent. 1H NMR spectroscopy verified

the presence of the nucleobases and quantified the degree of polymerization of the outer

blocks, based on the SEC molecular weight of the poly(n-butyl acrylate) precursor block

566 Robin, S.; Guerret, O.; Couturier, J. L.; Pirri, R.; Gnanou, Y. Synthesis and Characterization of Poly(styrene-b-n-butyl acrylate-b-styrene) Triblock Copolymers Using a Dialkoxyamine as Initiator. Macromolecules 2002, 35, 3844-8.

280

(Table 5.1, see Experimental for chemical shift values). Adenine-containing polymers with

increasing poly(n-butyl acrylate) molecular weight were denoted as A1-A3, and

thymine-containing polymers were denoted T1-T3. SEC analysis was also performed on the

nucleobase-functionalized triblock copolymers in THF, which confirmed narrow molecular

weight distributions and unimodal traces for the final triblock copolymers. However, SEC

was not suitable for the determination of the number average molecular weights of the

hydrogen bonding block due to the relatively short block lengths. Thus, 1H NMR

spectroscopy was used to calculate the molecular weights for the shorter hydrogen bonding

outer blocks. Blends of the complementary adenine- and thymine-containing polymers of

similar rubbery block molecular weights, denoted as A1/T1, A2/T2 and A3/T3, with a 1:1

ratio of adenine to thymine functional groups, were created via solution blending. These

blends enabled investigations into the effects of complementary hydrogen bonding on the

mechanical, rheological, thermal, and morphological properties of the triblock copolymers.

281

Table 5.1. Molecular weight data for nucleobase-functionalized block copolymers and

blends.

Polymer Triblock Molecular

Weights

Total Molecular

Weight (Mn)

Precursor

Mw/Mna

Weight %

nucleobase

monomer

A1 A1.5K-nBA16.5K-A1.5K 19.5K 1.26 15

A2 A2.8K-nBA23.7K-A2.8K 29.3K 1.11 19

A3 A2.3K-nBA62.3K-A2.3K 66.9K 1.23 7

T1 T1.8K-nBA13.9K-T1.8K 17.5K 1.23 21

T2 T2.0K-nBA23.7K-T2.0K 27.7K 1.11 14

T3 T1.4K-nBA69.9K-T1.4K 72.7K 1.22 4

aSEC: THF, 40 oC, MALLS

282

5.4.4 Complementary Hydrogen Bonding Interactions in Solution and Solid State

Hydrogen bonding interactions in polymers typically manifest themselves in both the

solid and solution state through changes in glass transition temperature, modulus, and

viscosity. Hydrogen bond association constants (Ka) are commonly characterized in the

solution state, using 1H NMR567 or FTIR568 spectroscopy to examine changes in the

chemical environment and bonding. These studies are typically performed in low dielectric

constant solvents such as chloroform or toluene, in order to facilitate stronger hydrogen

bonding interactions while maintaining solubility of the polar heterocycles.569 Our attempts

to study complementary hydrogen bonding in the block copolymers using 1H NMR

spectroscopy were unsuccessful due to disappearance of the resonances for the hydrogen

bonding groups in spectra collected in low polarity solvents such as CDCl3, presumably due

to solution aggregation. This was particularly evident for the adenine-functionalized block

copolymer (A2), where the nucleobase-functionalized blocks were visible in DMSO-d6, but

not in CDCl3. 1H NMR titration experiments of T3 with 9-octyladenine revealed expected

chemical shift changes for the thymine NH (from 10.4 to 11.7 ppm upon addition of 2.1

equiv 9-octyladenine). High solution viscosities and low concentrations of hydrogen

bonding groups also complicated FTIR analysis in solution.

567 Fielding, L. Determination of Association Constants (Ka) from Solution NMR Data. Tetrahedron 2000, 56, 6151-70. 568 Kyogoku, Y.; Lord, R. C.; Rich, A. An Infrared Study of Hydrogen Bonding between Adenine and Uracil Derivatives in Chloroform Solution. J Am Chem Soc 1967, 89, 496-504. 569 Sijbesma, R. P.; Beijer, F. H.; Brunsveld, L.; Folmer, B. J. B.; Hirschberg, J. H. K. K.; Lange, R. F. M.; Lowe, J. K. L.; Meijer, E. W. Reversible Polymers Formed from Self-Complementary Monomers Using Quadruple Hydrogen Bonding. Science 1997, 278, 1601-4.

283

Solution rheological experiments are often employed for the study of hydrogen bonding

systems, due to the sensitivity of viscosity to polymer structure in solution and the ability to

tune the strength of hydrogen bonding through solvent polarity.570571

- 572 Solution rheological

studies were performed on the hydrogen bonding block copolymers in chloroform as a

relatively low dielectric constant solvent. These studies were performed at a constant

nucleobase concentration of 1.20 M, which led to different polymer concentrations among the

samples due to slight differences in nucleobase block molecular weight. The presence of

the complementary hydrogen bonding interaction in solution was evident from the higher

solution viscosities of the blend, which possessed an intermediate polymer concentration due

to different nucleobase block molecular weights for the precursor polymers. The zero-shear

viscosity of the blend was more than three times higher than the individual polymers (Figure

5.5), which suggested significant intermolecular hydrogen bonding associations in solution.

At the concentrations studied, the polymer solutions exhibited Newtonian behavior with the

absence of shear thinning.

570 Sijbesma, R. P.; Beijer, F. H.; Brunsveld, L.; Folmer, B. J. B.; Hirschberg, J. H. K. K.; Lange, R. F. M.; Lowe, J. K. L.; Meijer, E. W. Reversible Polymers Formed from Self-Complementary Monomers Using Quadruple Hydrogen Bonding. Science 1997, 278, 1601-4. 571 Karikari, A.; Mather, B. D.; Long, T. E. Association of Star-Shaped Poly(D,L-lactide)s Containing Nucleobase Multiple Hydrogen Bonding. Biomacromolecules 2007, 8, 302-8. 572 Lange, R. F. M.; van Gurp, M.; Meijer, E. W. Hydrogen-bonded supramolecular polymer networks. J. Polym. Sci. Part A. Polym. Chem. 1999, 37, 3657-70.

284

1

10

100

0 200 400 600

Shear rate (1/s)

Visc

osity

(cP

)

T3A3A3/T3

ηo = 7.7 cP

ηo = 9.6 cP

ηo = 37 cP

Figure 5.5. Solution rheology of hydrogen bonding block copolymers (A3, T3 and their blend)

in chloroform at 25 oC.

285

The zero-shear solution viscosity of the hydrogen bonding triblock copolymers was also

studied as a function of concentration in the semi-dilute unentangled regime.573 In studying

the concentration dependence of the zero-shear specific solution viscosity, different scaling

exponents of the solution viscosities were observed compared to non-associating polymers.

Typically, the zero-shear viscosity scales as C1.25, for polymers below their entanglement

concentration (Ce), while above Ce, viscosity scales as C3.7 assuming that the polymer is

dissolved in a good solvent.574 As shown in Figure 5.6, the introduction of hydrogen

bonding groups led to scaling exponents of 1.4±0.02 and 1.6±0.02 for the thymine- and

adenine-functionalized triblock copolymers respectively due to the weak self association of

the nucleobases (KA-A ~ KT-T < 5 M-1).575 The errors in the scaling exponents were obtained

from statistical analysis of the linear regression, as described earlier.576 The blend of the two

polymers led to the highest exponent of 2.1±0.02 and the greater slope as a function of

hydrogen bonding strength was presumed to result from the concentration dependence of the

hydrogen bonding equilibrium.577 In the case of adenine and thymine hydrogen bonding

groups, neglecting self-association modes, the equilibrium can be written as:

Ka = [AT]/[A][T] [5.1]

573 de Gennes, P. G., Scaling Concepts in Polymer Physics. Cornell Univ: Ithaca, NY, 1979. 574 Colby, R. H.; Rubinstein, M. Two-parameter scaling for polymers in Θ solvents. Macromolecules 1990, 23, 2753-7. 575 Kyogoku, Y.; Lord, R. C.; Rich, A. The Effect of Substituents on the Hydrogen Bonding of Adenine and Uracil Derivatives. Proc Natl Acad Sci USA 1967, 57, 250-7. 576 Gaskins, K. Organic Self-Assembled Thin Films for Second Order Nonlinear Optics. Masters Thesis, Virginia Tech, 2004. 577 Sijbesma, R. P.; Beijer, F. H.; Brunsveld, L.; Folmer, B. J. B.; Hirschberg, J. H. K. K.; Lange, R. F. M.; Lowe, J. K. L.; Meijer, E. W. Reversible Polymers Formed from Self-Complementary Monomers Using Quadruple Hydrogen Bonding. Science 1997, 278, 1601-4.

286

where [A], [T] and [AT] are the concentrations of adenine, thymine and the associated

complex of adenine and thymine and Ka is the association constant (130 M-1).575 Thus, as

the concentration of the individual nucleobases increases, the concentration of the complex

must increase to satisfy the equilibrium. In the case of hydrogen bonding associations

between polymers with multiple nucleobases, this leads to increased effective molecular

weight of the supramolecular structures with increasing concentration. As Meijer has

established, the formation of associated structures may be considered as a non-covalent

step-growth process.578 Since solution viscosity is a strong function of molecular weight,

association is expected to lead to increased solution viscosity scaling exponents with

concentration. Long et al. previously observed higher scaling exponents above Ce for PMMA

which was randomly functionalized with ureidopyrimidone (UPy) quadruple hydrogen

bonding groups.579

578 Brunsveld, L.; Folmer, B. J. B.; Meijer, E. W.; Sijbesma, R. P. Supramolecular Polymers. Chem Rev 2001, 101, 4071-98. 579 McKee, M. G.; Elkins, C.; Long, T. E. Influence of self-complementary hydrogen bonding on solution rheology/electrospinning relationships. Polymer 2004, 45, 8705-15.

287

y = 3.19x2.13

y = 2.64x1.65

y = 1.21x1.43

1

10

100

0.1 1 10Concentration (wt%)

η sp

T3A3A3/T3

Figure 5.6. Zero-shear solution viscosities of the A3, T3 hydrogen bonding block copolymers

and their 1:1 A:T blend A3/T3 as a function of concentration.

288

Dynamic mechanical analysis (DMA) was utilized to examine the effects of hydrogen

bonding on the thermomechanical behavior of the individual triblock copolymers as well as

their complementary blends. Modulus versus temperature plots at a constant frequency (1 Hz)

confirmed the multiphase nature of the block copolymers (A3 and T3, Figure 5.7). The soft

phase glass transition temperature (Tg) occurred at -30 oC in each case whereas the hard

phase Tg occurred around 140 oC for the A3 and 110 oC for T3. This was consistent with

measurements of the Tg of adenosine-functionalized methacrylate homopolymers synthesized

by Haddleton et al., which possessed Tg values near 140 oC even for molecular weights below

10K.580 A blend of the complementary adenine and thymine-containing polymers (A:T = 1:1

mole ratio), cast from solution, revealed a comparable softening temperature (140 oC). The

absence of multiple softening transitions suggested the presence of a single hard phase

consisting of mixed adenine and thymine-containing polymer chains.

The samples were annealed at temperatures above the glass transitions (Tanneal = 135 oC),

in order to obtain thermodynamically favored morphologies, which may be inaccessible due

to strong hydrogen bonding interactions at ambient temperature. Block copolymers typically

require thermal annealing steps above the highest Tg, in order to achieve development of the

morphology. 581582

- 583 Due to strong intermolecular interactions, it was presumed that

580 Marsh, A.; Khan, A.; Haddleton, D. H.; Hannon, M. J. Atom Transfer Polymerization: Use of Uridine and Adenosine Derivatized Monomers and Initiators. Macromolecules 1999, 32, 8725-31. 581 Jeusette, M.; Leclere, P.; Lazzaroni, R.; Simal, F.; Vaneecke, J.; Lardot, T.; Roose, P. New “All-Acrylate” Block Copolymers: Synthesis and Influence of the Architecture on the Morphology and the Mechanical Properties. Macromolecules 2007, 40, 1055-65. 582 Marcos, A. G.; Pusel, T. M.; Thomann, R.; Pakula, T.; Okrasa, L.; Geppert, S.; Gronski, W.; Frey, H. Linear-Hyperbranched Block Copolymers Consisting of Polystyrene and Dendritic Poly(carbosilane) Block. Macromolecules 2006, 39, 971-7. 583 Tsarkova, L.; Horvat, A.; Krausch, G.; Zvelindovsky, A. V.; Sevink, G. J. A.; Magerle, R. Defect Evolution in Block Copolymer Thin Films via Temporal Phase Transitions. Langmuir 2006, 22, 8089-95.

289

nucleobase-functionalized block copolymers required annealing at higher temperatures. In

DMA experiments, the individual adenine- and thymine-functionalized triblock copolymers

did not exhibit significant change in their softening points upon annealing. In contrast with

the individual triblock copolymers, the blend (A3/T3) exhibited a significant increase in the

length of the rubbery plateau upon annealing, which extended to 150 oC (Figure 5.8). This

was attributed to formation of a hard phase consisting of associated adenine and thymine

functionalized blocks, that possessed greater thermomechanical integrity than the individual

components, which exhibited relatively weaker self-complementary (A-A, T-T) hydrogen

bonding. The presence of the associated hard phase was revealed with AFM studies for the

A2, T2, A2/T2 series.

For samples containing higher hard block weight fractions (A1, T1), a longer rubbery

plateau were observed (160 oC, not shown), and a similar, but less pronounced, enhancement

in hard phase thermal integrity for the blend upon annealing was also observed. Storage

modulus values at the rubbery plateau were also significantly higher (E’A1 = 0.6 MPa, E’T1 =

1.1 MPa, 80 oC) than those for the A3, T3 set due to the higher hard phase volume fraction.

290

-2

0

2

4

6

8

10

Tan

Del

ta

0.01

0.1

1

10

100

1000

10000

Log

Sto

rage

Mod

ulus

(MP

a)

-100 -50 0 50 100 150Temperature ( C)

A3A3 annealedT3T3 annealedA3/T3A3/T3 annealed

Universal V3.9A TA Instruments

Figure 5.7. Dynamic mechanical storage modulus and tan delta curves for adenine- and

thymine-functionalized block copolymers A3, T3 and their blend A3/T3 (A:T = 1:1). Black

lines represent samples that were annealed at 135 oC for 18 h under vacuum and gray lines

represent unannealed samples. DMA conditions: film tension mode, 1 Hz, 3 oC/min, N2.

a)

o

291

0.01

0.1

1

Log

Sto

rage

Mod

ulus

(MP

a)

50 100 150Temperature ( C)

A3A3 annealedT3T3 annealedA3/T3A3/T3 annealed


Figure 5.8. Expansion of high-temperature region of DMA storage modulus curves.

b)

annealing

o

292

5.4.5 Morphological Investigations of Nucleobase-Functionalized Block Copolymers and

Blends

AFM allows imaging of surface texture and morphology of microphase separated

structures and is frequently applied to block copolymer films.584,585 For both adenine- and

thymine-containing polymers, AFM revealed intriguing surface morphologies, which

consisted of hard domains of the nucleobase-functionalized styrene (light color) dispersed in

a soft matrix of poly(n-butyl acrylate) (dark color) (Figure 5.9). Adenine- and

thymine-functionalized block copolymers with identical rubber block molecular weights, (A2

and T2), as well as their solution-cast equimolar nucleobase (1:1 A:T) blends, were

spin-coated on silicon and imaged with AFM in tapping mode. Studies were conducted

before and after annealing at 155 oC, which facilitated morphological development of the

films. Unannealed samples exhibited microphase separation with generally poor shape

development of domains and lack of ordering. Annealing produced distinct morphological

features, with clear boundaries emerging between phases and development of short range

order. Although AFM does not provide a definitive identification of bulk morphology, the

thymine-containing block copolymer (T2) produced an apparent “end-on” cylindrical or

possibly spherical morphology (Figure 5.9). The presence of a cylindrical morphology was

consistent with the moderate weight fraction of the outer blocks (14 wt%). The positioning of

the hard domains appeared to indicate some degree of short-range hexagonally-closest

584 Hobbs, J. N.; Register, R. A. Imaging Block Copolymer Crystallization in Real Time with the Atomic Force Microscope. Macromolecules 2006, 39, 703-10. 585 Ott, H.; Abetz, V.; Altstadt, V.; Thomann, Y.; Pfau, A. Comparative study of a block copolymer morphology by transmission electron microscopy and scanning force microscopy. J Microscopy 2002, 205, 106-8.

293

packed (hcp) order. AFM images of A2 resembled cylindrical morphologies where cylinders

were lying in the plane of the image. The AFM image could possibly also be attributed to a

lamellar morphology, but the weight fraction of the hard phase was more consistent with a

cylindrical morphology. Hobbs and Register observed similar images corresponding to

cylindrical morphology in melts of poly(1,4-butadiene-b-3,4-isoprene).586 Tsarkova et al.

observed strikingly similar images of cylindrical morphologies of poly(styrene-b-butadiene)

melts. 587 The blend of the two polymers (A2/T2) exhibited a morphology with an

intermediate appearance, presumably indicating the presence of cylinders lying both in the

plane and perpendicular to the plane. The absence of macrophase separation in the blend

suggested the compatibility of the complementary nucleobase functionalized hard blocks due

to the hydrogen bonding ability of the adenine and thymine blocks. This supposition was

reinforced with SAXS analysis, which indicated an averaged, intermediate Bragg spacing,

and no evidence of multiple interdomain spacings, which is discussed in the following section.

Furthermore, Choo et al. showed that thymine- and adenine-containing small molecules

associate in the solid state into co-crystalline forms, upon simple grinding of a blend of the

individual crystalline solids.588

586 Hobbs, J. N.; Register, R. A. Imaging Block Copolymer Crystallization in Real Time with the Atomic Force Microscope. Macromolecules 2006, 39, 703-10. 587 Tsarkova, L.; Horvat, A.; Krausch, G.; Zvelindovsky, A. V.; Sevink, G. J. A.; Magerle, R. Defect Evolution in Block Copolymer Thin Films via Temporal Phase Transitions. Langmuir 2006, 22, 8089-95. 588 Etter, M. C.; Reutzel, S. M.; Choo, C. G. Self-organization of Adenine and Thymine in the Solid State. J Am Chem Soc 1993, 115, 4411-2.

294

Figure 5.9. Tapping mode AFM phase images of thymine- (T2) and adenine-functionalized

(A2) polymers before and after annealing as well as A2/T2 blend. Samples were spin-coated

on a silicon wafer, from chloroform solution. Annealing was performed at 155 oC under

vacuum for 18 h. Film thickness ~ 100 nm. Images are 500 nm x 500 nm.

155 oC

155 oC

A2

A2/T2

blend

T2

295

Analogous AFM studies were conducted for the A1, T1 and A1/T1 set (Figure 5.10)

which contained slightly higher nucleobase weight fractions (15-21 wt% for A1, T1 and

A1/T1 versus 14-19 wt% for the A2, T2 and A2/T2 set) and slightly shorter rubber block

molecular weights (13.9K or 15.9K vs. 23.7K). As seen with the A2 and T2 series, the

unannelead samples exhibited poor morphological development. Annealing at 155 oC resulted

in images that were similar to A2, resembling the “in plane” cylindrical morphology.

Interestingly, the A1/T1 blend exhibited the least clear surface texture, possibly due to the

strength of the complementary A-T hydrogen bonding interactions preventing clear

morphological development. The higher softening temperatures for the hard phases of T1

and T2 (160 oC), suggested that annealing at 155 oC was insufficient. In order to probe the

effect of annealing at higher temperatures on block polymers containing the higher levels of

nucleobases, annealing experiments were conducted on the A1, T1, A1/T1 series at

temperatures near 200 oC (Figure 5.10). Interestingly, annealing at temperatures near 200

oC enabled organization into “end-on” cylindrical morphologies for A1 and A1/T1 at the

surface, and hcp ordering was observed as evidenced from the hexagonal shape of the Fourier

transform of the AFM phase images. For the T1 sample, a well ordered cylindrical

“in-plane” surface morphology was observed at 190 oC, followed by the beginning of a

transition to “end-on” arrangement at 210 oC. SAXS experiments (discussed in the next

section) conducted on the A1, T1 and A1/T1 set, annealed at 200 oC and 155 oC confirmed

the cylindrical morphology in all cases. The hindered rearrangement of the thymine-

containing polymer may have resulted from the fact that it possessed the highest nucleobase

weight fraction (19 wt%) and lowest poly(n-butyl acrylate) block molecular weight (13.9K).

296

Roose et al. also observed a transition upon annealing of “cylinders in the plane” to “end-on”

cylinders for a poly(methyl methacrylate-b-methyl acrylate-co-ethylhexyl acrylate-b-methyl

methacrylate).589 The higher surface energy of the PMMA blocks was thought to result in the

minimization of surface area of the hard domains, driving the system to the “end-on”

morphology. In the present system, it is assumed that the polar nucleobase-containing blocks

possess a higher surface energy than the poly(n-butyl acrylate) block, resulting in similar

behavior.

589 Jeusette, M.; Leclere, P.; Lazzaroni, R.; Simal, F.; Vaneecke, J.; Lardot, T.; Roose, P. New “All-Acrylate” Block Copolymers: Synthesis and Influence of the Architecture on the Morphology and the Mechanical Properties. Macromolecules 2007, 40, 1055-65.

297

Figure 5.10. Tapping mode AFM phase images of A1, T1 and A1/T1 blend. Samples were

spin-coated on silicon wafers, from chloroform solution. Annealing was performed at

A1 T1 A1/T1

125 nm 125 nm 125 nm

A1

A1

125 nm

125 nm

T1

125 nm

A1/T1

T1

125 nm 125 nm

A1/T1

T1

125 nm

125 nm

210 oC

190 oC200 oC 210 oC

155 oC155 oC155 oC

25 oC25 oC25 oC

298

temperatures indicated in the lower left corners of each image, under vacuum for 18 h. Film

thicknesses ~ 100 nm. Images are 500 nm x 500 nm. Setpoint ratio ~ 0.6. Insets are Fourier

transforms (FFTs) of the phase images.

299

While AFM was successful in characterizing the surface morphology of the block

copolymers, SAXS enabled characterization of the bulk morphology of the

nucleobase-functionalized block copolymers. SAXS experiments were conducted on

individual adenine- and thymine-functionalized triblock copolymer as well as the

corresponding 1:1 A:T blends. SAXS confirmed the presence of microphase separation in all

hydrogen bonding triblock copolymers, through the presence of a primary scattering

maximum at scattering vector q*. The primary scattering maximum was used to determine

the interdomain (Bragg) spacing present in each sample (d = 2π/q*), shown in Table 5.2. The

interdomain spacing measured from SAXS (12-20 nm) were similar to those observed with

AFM. Additional secondary scattering maxima were observed in some cases, allowing

morphological assignments. In the case of ~15K poly(n-butyl acrylate) block samples (A1,

T1), each individual polymer produced cylindrical morphology, as evidenced from the

positions of the scattering maxima (q/q* = 1, √3, √7 )590 (Figure 5.11). The expected

maximum at q/q* = 2 was not observed, but was believed to exist as a small shoulder on the

peak at q/q* = √3. The blend of the complementary block copolymers (A:T = 1:1) produced a

similar cylindrical morphology with a Bragg spacing that was intermediate between the

individual polymers. This trend of intermediate Bragg spacings for the blends was observed

for the A2, T2 set as well and suggested the intimate mixing of the complementary hydrogen

bonding hard blocks producing an averaged interdomain spacing. For the ~24K

poly(n-butyl acrylate) block samples (A2, T2), secondary scattering peaks were not clearly

resolved, which may be due to the casting conditions. The highest rubber block molecular

590 Mani, S.; Weiss, R. A.; Hahn, S. F.; Williams, C. E.; Cantino, M. E.; Khairallah, L. H. Microstructure of block copolymers of polystyrene and poly(ethylene-alt-propylene). Polymer 1998, 10, 2023-33.

300

weight samples (A3, T3) produced multiple scattering maxima, which were also attributed to

cylindrical morphology.

301

Table 5.2. Small-angle X-ray scattering results for hydrogen bonding block copolymers.

Polymer Triblock Molecular

Weights

wNua

(%)

q*

(A-1)

d (nm) q2 (A-1) q3 (A-1) Morphologyb

A1 A1.5K-nBA16.5K-A1.5K 15 0.042 15.0 0.072 0.112 cyl

A2 A2.8K-nBA23.7K-A2.8K 19 0.044 14.3 - - -

A3 A2.3K-nBA62.3K-A2.3K 7 0.029 21.7 0.052 - cyl

T1 T1.8K-nBA13.9K-T1.8K 21 0.039 16.1 0.069 0.111 cyl

T2 T2.0K-nBA23.7K-T2.0K 14 0.052 12.1 - - -

T3 T1.4K-nBA69.9K-T1.4K 4 0.032 19.6 0.054 - cyl

A1/T1 N/A 18 0.040 15.7 0.074 0.121 cyl

A2/T2 N/A 16 0.046 13.7 - - -

A3/T3 N/A 6 0.033 19.0 0.058 - cyl

a Weight percent of nucleobase-functionalized block.

bAssignments from SAXS maxima.

302

0.001

0.01

0.1

1

10

0 0.05 0.1 0.15q (A-1)

Inte

nsity

A1

T1

A1/T1

Figure 5.11. SAXS scattering profiles for nucleobase-containing polymers (A1, T1) and their

1:1 A:T blend. All samples annealed under vacuum at 155 oC for 18 h. Scattering maxima in

terms of q/q* are denoted with arrows.

1

√3

√7

303

Annealing studies with subsequent SAXS analysis were performed on the

thymine-containing triblock copolymer with the highest nucleobase weight fraction (T1, 21

wt%). As the annealing temperature increased, the scattering profile changed dramatically

(Figure 5.12). Narrowing of the scattering maxima and the appearance of several readily

discernable secondary maxima were observed. Annealing at 200 oC appeared to result in the

clearest development of morphology in this sample, revealing scattering maxima of q/q* = 1,

√3, 2, √7, 3, 2√3, which corresponded to hexagonal closest packed (hcp) cylindrical

morphology. Furthermore, the scattering maximum at q/q* = 2 was observed as a clear

shoulder on the maximum at q/q* = √3. This suggested that elevated temperatures near 200

oC were necessary to achieve well-developed morphologies for the triblock copolymers with

higher nucleobase weight fraction.

304

0.1

1

10

100

1000

0 0.05 0.1 0.15

q (A-1)

Scat

teri

ng I

nten

sity

25 C

155 C

200 C

Figure 5.12. Effect of annealing conditions on thymine-containing triblock copolymer (T1)

sample. Scattering maxima in terms of q/q* are denoted with arrows.

1

√3

2 √7

3 2√3

o

o

o

305

The adenine-containing triblock copolymer A1, and blend of adenine- and

thymine-containing block copolymers (A1/T1) were also annealed at 200 oC, but did not

exhibit the development of the order apparent in the T1 sample annealed at 200 oC. SAXS

profiles of adenine-containing samples that were annealed at 200 oC resembled samples

annealed at 155 oC. This may have resulted from possible crosslinking side reactions

including nucleophilic attack of the adenine NH2 to the n-butyl acrylate ester. In dynamic

mechanical measurements, heating of the adenine containing polymers above 200 oC resulted

in crosslinking as evidenced from increasing storage modulus (E’) and insolubility in solvents

which previously dissolved the polymers. Melt rheological experiments at 150 and 160 oC

indicated thermal stability at these reduced temperatures, and nearly constant shear storage

modulus (G’) and viscosity values were observed in the melt at 160 oC.

5.4.6 Introduction of Guest Molecules to Hydrogen Bonding Block Copolymers

Hydrogen bonding interactions will facilitate the introduction of guest molecules

containing complementary recognition units. Others have shown the recognition of guest

molecules through hydrogen bonding interactions in both solution591 and the solid state.592

Rotello et al. have used three-point hydrogen bonding between diacyldiaminopyridines and

thymine to attach guest molecules containing flavin593 or POSS592 to polystyrene. Guest

591 Thibault, R. J.; Hotchkiss, P. J.; Gray, M.; Rotello, V. M. Thermally Reversible Formation of Microspheres through Non-Covalent Polymer Cross-Linking. J Am Chem Soc 2003, 125, 11249-52. 592 Carroll, J. B.; Waddon, A. J.; Nakade, H.; Rotello, V. M. “Plug and Play” Polymers. Thermal and X-ray Characterizations of Noncovalently Grafted Polyhedral Oligomeric Silsesquioxane (POSS)-Polystyrene Nanocomposites. Macromolecules 2003, 36, 6289-91. 593 Ilhan, F.; Galow, T. H.; Gray, M.; Clavier, G.; Rotello, V. M. Giant Vesicle Formation through Self-Assembly of Complementary Random Copolymers. J Am Chem Soc 2000, 122, 5895-6.

306

molecules also increase the solubility of hydrogen bonding polymers through screening

self-association of the polymer, thereby maintaining the homogeneity during polymerization

reactions.594

A complementary alkylated adenine-containing small molecule guest (9-octyladenine,

see Figure 5.14 for structure) was introduced into a thymine-containing block copolymer (T2

and T3). 1H NMR titrations of T3 with 9-octyladenine indicated shifts in the peak position of

the thymine NH proton to higher field (from 10.4 to 11.7 ppm) upon the addition of 2.2

equivalents of 9-octyladenine (Figure 5.13). The curvature of the chemical shift data with

increasing adenine concentration was consistent with typical NMR titration experiments in

the literature.595 Fitting this chemical shift data using the Benesi-Hildebrande method595

produced an association constant of Ka = 40 M-1 and demonstrated the non-covalent

attachment of 9-octyladenine in the solution state. Unlike the association of the

complementary triblock copolymers, where associations led to disappearance of the

nucleobase resonances, the attachment of the guest molecule does not create restrictions on

the motion of the polymer in solution, which makes 1H NMR spectroscopic observation of

the hydrogen bonding interaction feasible.

594 Stubbs, L. P.; Weck, M. Towards a Universal Polymer Backbone: Design and Synthesis of Polymeric Scaffolds Containing Terminal Hydrogen-Bonding Recognition Motifs at Each Repeating Unit. Chem Eur J 2003, 9, 992-9. 595 Fielding, L. Determination of Association Constants (Ka) from Solution NMR Data. Tetrahedron 2000, 56, 6151-70.

307

10

10.5

11

11.5

12

12.5

0 10 20 30

[9-octyladenine] (mM)

δ Th

ymin

e N

H (

ppm

)

Figure 5.13. Chemical shift changes during introduction of 9-octyladenine to a

thymine-containing triblock copolymer (T3).

N

N

NH2

N

N

CH2 CH37

9-octyladenine

308

For blends of 9-octyladenine with T2 in the solid state, AFM images indicated selective

incorporation of the small molecule into the adenine-containing hard domains, as evidenced

from increased phase contrast and greater hard phase continuity (Figure 5.14). The addition

of 9-octyladenine present in the samples corresponded to 5 wt% for 0.4 equivalents, and 24

wt% for 2.2 equivalents. Future efforts will be devoted to studying non-covalent attachment

of other functionalities via hydrogen bonding interactions.

309

Figure 5.14. Tapping mode AFM images of unannealed thymine-functionalized block

copolymer (T2) spin coated on a silicon wafer from chloroform solutions containing (a) 0, (b)

0.4 and (c) 2.2 equivalents of 9-octyladenine.

310

5.5 Conclusions

Nucleobase-functionalized triblock copolymers with adenine and thymine containing

outer blocks were synthesized for the first time via nitroxide mediated radical polymerization

involving a novel difunctional initiator. Hydrogen bonding interactions in blends of

complementary polymers led to associations in solution that were manifested through

dramatic increases in viscosity. Increased solution viscosity scaling exponents with

concentration indicated the influence of the hydrogen bonding equilibrium through increased

effective molecular weight. In the solid state, hydrogen bonding led to compatibilization of

the blends through the formation of an associated A-T hard phase. Morphological

investigations of the individual block copolymers as well as their complementary blends

revealed intermediate domain spacings and surface textures for blends of the complementary

block copolymers. The introduction of complementary guest molecules resulted in selective

uptake into nucleobase containing domains.

5.6 Acknowledgement

The authors would like to thank Funda Senyurt for helpful discussions during the

writing of the manuscript. The authors would like to acknowledge Kraton Polymers for

complementary funding and Dr. Carl Willis of Kraton Polymers for insightful discussions.

This material is based upon work supported by, or in part by, the U.S. Army Research

Laboratory and the U.S. Army Research Office under grant number DAAD19-02-1-0275


311

Chapter 6. Multiple Hydrogen Bonding for the Non-covalent

Attachment of Ionic Functionality in Block Copolymers

(Mather, B.D.; Baker, M.B.; Beyer, F.L.; Green, M.D.; Berg, M.A.G.; Long T.E.,

Macromolecules, submitted)

6.1 Abstract

Multiple hydrogen bonding interactions were utilized to reversibly attach nucleobase

functional phosphonium salt guests to complementary functionalized triblock copolymers.

Novel adenine-containing triblock copolymers were synthesized via nitroxide mediated

polymerization using a novel difunctional alkoxyamine initiator. Ionic interactions were

introduced via a novel uracil-containing phosphonium salt (UP+), which formed optically

clear blends with the adenine functional block copolymer. An apparent 3.4 fold decrease in

solution viscosity upon addition of UP+ to the block copolymer in chloroform (4.2 wt%, 25

°C) suggested a screening of adenine-adenine hydrogen bonding interactions.

Morphological investigations revealed unique surface textures for the UP+ block copolymer

blends compared with the pure adenine-containing block copolymer. Small-angle X-ray

scattering revealed a transition from cylindrical to lamellar morphologies upon incorporation

of the phosphonium salt. Dynamic mechanical measurements indicated an increased

rubbery plateau due to the greater hard phase volume fraction, and a softening at lower

temperatures than the pure adenine-containing block copolymer due to hydrogen bond

screening.

312

6.2 Introduction

The introduction of electrostatic interactions to diverse macromolecular architectures

has received significant attention for several decades.596597

-598

599 Ionomers, which are defined as a

class of lightly charged (≤15 mol%) ion-containing polymers, possess electrostatic

interactions with enthalpies near ~200 kJ/mol.600 The Coulombic forces enable the formation

of nanometer-scale aggregates 601 resulting in improved thermo-mechanical properties,

increased toughness, improved chemical resistance, and opportunities for self-healing

substrates.602,603 A further advantage of ion-containing polymers is the ability to conduct ions,

which suggests applications in ion-conducting membranes, fuel cells, electromechanical

devices, water purification membranes, and breathable textiles for protection from chemical

and biological reagents.604605

-606

607

596 Eisenberg, A.; Hird, B.; Moore, R. B. A New Multiplet-Cluster Model for the Morphology of Random Ionomers. Macromolecules 1990, 23, 4098-107. 597 Mani, S.; Weiss, R. A.; Williams, C. E.; Hahn, S. F. Microstructure of Ionomers Based on Sulfonated Block Copolymers of Polystyrene and Poly(ethylene-alt-propylene). Macromolecules 1999, 32, 3663-70. 598 Lowry, S. R.; Mauritz, K. A. An investigation of ionic hydration effects in perfluorosulfonate ionomers by Fourier transform infrared spectroscopy. J. Am. Chem. Soc. 1980, 102, 4665-7. 599 Kabanov, A. V.; Bronich, T. K.; Kabanov, V. A.; Yu, K.; Eisenberg, A. Spontaneous Formation of Vesicles from Complexes of Block Ionomers and Surfactants. J. Am. Chem. Soc. 1998, 120, 9941-2. 600 Hird, B.; Eisenberg, A. Sizes and Stabilities of Multiplets and Clusters in Carboxylated and Sulfonated Styrene Ionomers. Macromolecules 1992, 25, 6466-74. 601 Benetatos, N. M.; Heiney, P. A.; Winey, K. I. Reconciling STEM and X-ray Scattering Data from a Poly(styrene-ran-methacrylic acid) Ionomer: Ionic Aggregate Size. Macromolecules 2006, 39, 5174-6. 602 Eisenberg, A.;Kim, J.-S.; Introduction to Ionomers; Wiley: New York 1998. 603 Kalista, S. J. M.S. Thesis, Virginia Tech, 2003. 604 Hickner, M. A.; Ghassemi, H.; Kim, Y. S.; Einsla, B. R.; McGrath, J. E. Alternative Polymer Systems for Proton Exchange Membranes (PEMs). Chem Rev 2004, 104, 4587-611. 605 Akle, B.; Leo, D. J.; Hickner, M. A.; McGrath, J. E. Correlation of capacitance and actuation in ionomeric polymer transducers. J Mater Sci 2005, 40, 3715-24. 606 Rivin, D.; Meermeier, G.; Schneider, N. S.; Vishnyakov, A.; Neimark, A. V. Simultaneous Transport of Water and Organic Molecules through Polyelectrolyte Membranes. J. Phys. Chem. B 2004, 108, 8900-9. 607 Zhou, J.; Li, Z.; Liu, G. Diblock Copolymer Nanospheres with Porous Cores. Macromolecules 2002, 35, 3690-6.

313

Despite the attractive physical properties of ionomers, melt processing often suffers due

to relatively high viscosities that are attributed to ionic aggregates (which can persist to

temperatures exceeding 300 oC).608 Earlier efforts have attempted to address this potential

limitation, and for example, the processability of sulfonated

poly(ethylene-co-propylene-co-diene) (EPDM) improved upon the addition of zinc stearate,

which “plasticized” the ionic aggregates. 609 Herein, we provide the first report of

complementary hydrogen bonding as a reversible linkage for attachment of phosphonium

cations to block copolymers (Figure 6.1). This manuscript demonstrates the general concept

of reversible ionic site attachment to block copolymers, which dissociate from the block

copolymer above the dissociation temperature for hydrogen bonding.

608 Lu, X.; Steckle, W. P.; Hsiao, B.; Weiss, R. A. Thermally Induced Microstructure Transitions in a Block Copolymer Ionomer. Macromolecules 1995, 28, 2831-9. 609 Duvdevani, I.; Lundberg, R. D.; Wood-Cordova, C.; Wilkes, G. L., Coulombic Interactions in Macromolecular Systems. In ACS Symposium Series, Eisenberg, A.; Bailey, F. E., Eds. American Chemical Society: Washington DC, 1986; Vol. 302, pp 185-99.

314

Figure 6.1. Reversible attachment of UP+ phosphonium salt to complementary nucleobase

functionalized block copolymers.

UP+

PR3+

X-

D A

NN

HNN

N

NH

O

N

OH

H

P+ Cl-oct

octoct

Δ

D A D A D A D A

D A

PR3+

X-

D A

PR3+

X-

D A

PR3+

X-

D A

PR3+

X-

D A =

315

Hydrogen bonding, in contrast to non-directional electrostatic interactions, exhibits

lower enthalpies (10-40 kJ/mol) and greater specificity, which enables molecular recognition

and lower melt viscosities using multiple hydrogen bonding arrays such as ureido

pyrimidones (UPy) and nucleobase pairs.610611612

-613614

615 This manuscript describes the synergy of

complementary hydrogen bonding in nanostructured block copolymers with guest molecules

containing electrostatic interactions. Earlier researchers have reported coordination of metal

sulfonates to pyridine containing block copolymers, however, the potential synergy of

complementary hydrogen bonding with electrostatic interactions was not reported.616 Other

researchers have reported the reversible attachment of neutral guest molecules via hydrogen

bonding interactions and for example, non-covalent attachment of mesogens resulted in

supramolecular liquid crystalline assemblies.617618

-619620

621

610 Sijbesma, R. P.; Beijer, F. H.; Brunsveld, L.; Folmer, B. J. B.; Hirschberg, J. H. K. K.; Lange, R. F. M.; Lowe, J. K. L.; Meijer, E. W. Reversible Polymers Formed from Self-Complementary Monomers Using Quadruple Hydrogen Bonding. Science 1997, 278, 1601-4. 611 Yamauchi, K.; Lizotte, J. R.; Hercules, D. M.; Vergne, M. J.; Long, T. E. Combinations of Microphase Separation and Terminal Multiple Hydrogen Bonding in Novel Macromolecules. J Am Chem Soc 2002, 124, 8599-604. 612 Mather, B. D.; Lizotte, J. R.; Long, T. E. Synthesis of Chain End Functionalized Multiple Hydrogen Bonded Polystyrenes and Poly(alkyl acrylates) Using Controlled Radical Polymerization. Macromolecules 2004, 37, 9331-7. 613 Yamauchi, K.; Lizotte, J. R.; Long, T. E. Synthesis and Characterization of Novel Complementary Multiple-Hydrogen Bonded (CMHB) Macromolecules via a Michael Addition. Macromolecules 2002, 35, 8745-50. 614 Nair, K. P.; Pollino, J. M.; Weck, M. Noncovalently Functionalized Block Copolymers Possessing Both Hydrogen Bonding and Metal Coordination Centers. Macromolecules 2006, 39, 931-40. 615 Noro, A.; Nagata, Y.; Tsukamoto, M.; Hayakawa, Y.; Takano, A.; Matsushita, Y. Novel Synthesis and Characterization of Bioconjugate Block Copolymers Having Oligonucleotides. Biomacromolecules 2005, 6, 2328-33. 616 Valkama, S.; Ruotsalainen, T.; Kosonen, H.; Ruokolainen, J.; Torkkeli, M.; Serimaa, R.; ten Brinke, G.; Ikkala, O. Amphiphiles Coordinated to Block Copolymers as a Template for Mesoporous Materials. Macromolecules 2003, 36, 3986-91. 617 Kumar, U.; Kato, T.; Fréchet, J. M. J. Use of intermolecular hydrogen bonding for the induction of liquid crystallinity in the side chain of polysiloxanes. J. Am. Chem. Soc. 1992, 114, 6630-9.

316

Phosphonium cations have received recent attention in our laboratories due to higher

thermal stabilities relative to ammonium analogs. Earlier evidence indicates that the onset

of decomposition of tetraoctylammonium bromide occurs at 170 ºC due to Hofmann

elimination, whereas the analogous phosphonium salt exhibits thermal stability to 260

ºC.622,623 Despite bulky organic substitution on the phosphonium cation, others have recently

reported random copolymers containing covalently bound phosphonium cations, which result

in nanoscale ionic aggregation and concomitant thermoplastic elastomeric behavior.624,625

Novel hydrogen bonding triblock copolymers containing adenine were synthesized via

nitroxide mediated polymerization. A novel difunctional initiator, which does not introduce

hydrolytically unstable ester linkages that lead to molecular weight loss, permitted the

618 Thibault, R. J.; Hotchkiss, P. J.; Gray, M.; Rotello, V. M. Thermally Reversible Formation of Microspheres through Non-Covalent Polymer Cross-Linking. J Am Chem Soc 2003, 125, 11249-52. 619 van Ekenstein, G. A.; Polushkin, E.; Nijland, H.; Ikkala, O.; ten Brinke, G. Shear Alignment at Two Length Scales: Comb-Shaped Supramolecules Self-Organized as Cylinders-within-Lamellar Hierarchy. Macromolecules 2003, 36, 3684-8. 620 Kato, T.; Kihara, H.; Ujiie, S.; Uryu, T.; Frechet, J. M. J. Structures and Properties of Supramolecular Liquid-Crystalline Side-Chain Polymers Built through Intermolecular Hydrogen Bonds. Macromolecules 1996, 29, 8734-9. 621 Burd, C.; Weck, M. Self-Sorting in Polymers. Macromolecules 2005, 38, 7225-30. 622 Xie, W.; Xie, R.; Pan, W. P.; Hunter, D.; Koene, B.; Tan, L. S.; Vaia, R. Thermal Stability of Quaternary Phosphonium Modified Montmorillonites. Chem. Mater. 2002, 14, 4837-45. 623 Burch, R. R.; Manring, L. E. N-Alkylation and Hofmann elimination from thermal decomposition of R4N+ salts of aromatic polyamide polyanions: synthesis and stereochemistry of N-alkylated aromatic polyamides. Macromolecules 1991, 24, 1731-5. 624 Parent, J. S.; Penciu, A.; Guillen-Castellanos, A.; Liskova, A.; Whitney, R. A. Synthesis and Characterization of Isobutylene-Based Ammonium and Phosphonium Bromide Ionomers. Macromolecules 2004, 37, 7477-83. 625 Arjunan, P.; Wang, H.-C.; Olkusz, J. A., Functional Polymers. American Chemical Society: Washington DC, 1998; Vol. 704, p 199-216.

317

formation of symmetric outer blocks, reduced the number of subsequent monomer additions,

and enabled a single crossover reaction.

6.3 Experimental

6.3.1 Materials



Diethyl-meso-2,5-dibromoadipate (98%), copper (I) bromide (99.999%),

N,N,N’,N”,N”-pentamethyldiethylenetriamine (PMDETA, 98%), trioctylphosphine (90%)

and 6-chloromethyluracil (98%) were purchased from Aldrich and used without further

purification. Copper powder (45 μm, 99%) was purchased from Acros and used as received.

DEPN nitroxide, 626 Styryl-DEPN, 627 and 9-vinylbenzyl adenine 628 were synthesized

according to the previous literature.

6.3.2 Synthesis of 6-(trioctylphosphonium methyl)uracil chloride (UP+)

6-chloromethyluracil (1.001 g, 6.232 mmol) and trioctylphosphine (3.25 mL, 2.70 g,

7.29 mmol) were charged to a 100 mL round-bottomed flask containing a magnetic stirbar.

626 Grimaldi, S.; Finet, J. P.; Le Moigne, F.; Zeghdaoui, A.; Tordo, P.; Benoit, D.; Fontanille, M.; Gnanou, Y. Acyclic B-Phosphonylated Nitroxides: A New Series of Counter-Radicals for "Living"/Controlled Free Radical Polymerization. Macromolecules 2000, 33, 1141-7. 627 Diaz, T.; Fischer, A.; Jonquieres, A.; Brembilla, A.; Lochon, P. Controlled Polymerization of Functional Monomers and Synthesis of Block Copolymers Using a B-Phosphonylated Nitroxide. Macromolecules 2003, 36, 2235-41. 628 Srivatsan, S. G.; Parvez, M.; Verma, S. Modeling of Prebiotic Catalysis with Adenylated Polymeric Templates: Crystal Structure Studies and Kinetic Characterization of Template-Assisted Phosphate Ester Hydrolysis. Chem. Eur. J. 2002, 8, 5184-91.

318

Ethanol (40 mL) was added and a condenser was fitted to the flask. The reactions was

heated to reflux using an external oil bath for 24 h. Excess solvent was removed using

rotary evaporation. The resulting waxy solid was washed with diethyl ether and was dried

overnight at room temperature under high vacuum. UP+ was obtained as a light brown solid

(m.p. 179-181 °C) in 88% yield. 1H NMR (400 MHz, DMSO-d6, 25 °C) δ (ppm): 0.86 (t, 9H,

J = 6.8 Hz), 1.26 (m, 24H), 1.37 (m, 6H), 1.49 (m, 6H), 2.37 (m, 6H), 3.77 (d, 2H, J = 15 Hz),

5.55 (m, 1H), 11.15 (s, 1H), 11.47 (s, 1H). 13C NMR (101 MHz, DMSO-d6, 25 °C) δ (ppm):

13.96, 17.61, 18.06, 20.52, 22.08, 28.27, 28.8, 30.06, 31.22, 102.08, 145.18, 150.95, 163.37.

31P NMR (162 MHz, DMSO-d6, 25 °C) δ (ppm): 33.68 ppm. FAB MS: m/z = 495.4056

[M-Cl]+ (experimental), m/z = 495.41 (theoretical).

6.3.3 Synthesis of DEPN2 Difunctional Alkoxyamine Initiator

DEPN nitroxide (2.0 g, 6.8 mmol) and diethyl-meso-2,5-dibromoadipate (1.36 g, 3.8

mmol) were charged to a one-necked 100-mL round-bottomed flask containing a magnetic

stirbar. Dichloromethane (30 mL) was added and the solution was degassed with three

freeze-pump-thaw cycles. In a second 100-mL round-bottomed flask, PMDETA (2.34 g, 13.6

mmol) was dissolved in 20 mL CH2Cl2 and subjected to the same degassing. In a third

100-mL round-bottomed flask containing a stirbar, CuBr (0.78 g, 5.47 mmol) and Cu powder

(0.35 g, 5.47 mmol) were purged with nitrogen gas. After degassing, the liquid reagents were

cannulated into the flask containing the copper powder and CuBr. The reaction was stirred

for 24 h at 25 oC under nitrogen, diluted with CH2Cl2 (200 mL), and washed repeatedly with

water (10 x 100 mL), to remove copper compounds. The organic layer was then dried over

319

sodium sulfate and evaporated. The product was separated on silica, eluting with ethyl

acetate : hexane (1:1). DEPN2 was isolated as a mixture of diastereomers. Purified yield =

49%. 1H NMR (400 MHz, CDCl3, 25 °C) δ (ppm): 1.0-1.2 (s, tBu, 36H), 1.2-1.4 (m, ester

CH3, 18H), 1.6-2.4 (br, linker CH2, 4H), 3.1-3.6 (m, DEPN CH, 2H), 3.9-4.2 (m, CH3, 12H),

4.4-4.5 (m, COCH, 2H). 13C NMR (101 MHz, CDCl3, 25 °C) δ (ppm): 172.74, 171.46, 86.74,

86.31, 81.87, 81.52, 77.20, 76.85, 75.31, 70.27, 69.99, 68.90, 68.62, 62.30, 62.23, 62.03,

61.96, 61.66, 61.57, 60.62, 60.40, 60.32, 60.27, 60.22, 58.89, 58.82, 35.64, 35.58, 35.49,

35.21, 35.16, 35.09, 34.48, 30.18, 30.12, 29.93, 29.89, 29.44, 29.38, 28.12, 27.95, 27.89,

27.56, 27.53, 26.96, 26.67, 26.52, 26.46, 16.47, 16.41, 16.35, 16.32, 16.14, 16.08, 14.03,

13.98, 13.90. 31P NMR (162 MHz, CDCl3, 25 °C) δ (ppm): 25.82, 25.63, 25.59, 25.20, 25.00,

24.91. FAB MS: m/z = 789.4842 [M+H]+ experimental, m/z = 789.48 theoretical. No peak for

the monofunctional initiator was observed (m/z = 574.5).

Meso diastereomer of DEPN2: The meso diastereomer was isolated from the partly

crystalline first fractions obtained during chromatographic purification of DEPN2. Further

separation was achieved via washing the crystals with hexane. m.p. = 139.5-141.5 °C. 1H

NMR (400 MHz, CDCl3, 25 °C) δ (ppm): 1.03 (s, N-tBu, 18H), 1.06 (s, C-tBu, 18H), 1.24

(m, ester CH3, 18H), 1.55-2.40 (br, linker CH2, 4H), 3.18 (d, J = 25 Hz, DEPN CH, 2H),

3.85-4.20 (m, OCH2, 12H), 4.25-4.46 (br, OCH, 2H). 13C NMR (101 MHz, CDCl3, 25 °C)

δ (ppm): 172.89, 86.65, 69.71(d, J = 138 Hz), 61.80 (d, J = 6.1 Hz), 61.05 (d, J = 95 Hz),

58.69 (d, J = 7 Hz), 35.59 (d, J = 5.4 Hz), 29.31 (d, J = 6.2 Hz), 28.57, 27.94, 16.31 (dd, J1 =

28.4 Hz, J2 = 6.2 Hz), 13.95. 31P NMR (162 MHz, CDCl3, 25 °C) δ (ppm): 25.67.

320

6.3.4 Polymerization of n-Butyl Acrylate from DEPN2 Nitroxide

DEPN2 alkoxyamine (212 mg, 0.269 mmol) and DEPN nitroxide (31 mg, 0.106 mmol)

were weighed into a 100-mL round-bottomed flask containing a magnetic stirbar. The flask

was sealed with a three-way joint allowing syringing of reagents and application of vacuum

and nitrogen. The flask was evacuated to 60 mtorr and refilled with high-purity nitrogen three

times. Purified n-butyl acrylate (30 mL, 209 mmol) was added via syringe and the mixture

was degassed with repeated freeze-pump-thaw cycles. Finally, the flask was immersed in an

oil bath at 122 oC for 3 h. After the polymerization, residual monomer was removed with

high vacuum stripping. Yield = 5.82 g polymer (Conversion = 22%). SEC analysis revealed

molecular weight data Mn = 16,500, Mw/Mn = 1.24.

6.3.5 Synthesis of Adenine Containing Block Copolymer

Poly(n-butyl acrylate) homopolymer (4.83 g, Mn = 16,500) and 9-vinylbenzyl adenine13

(9-VBA, 0.990 g, 3.94 mmol) were added to a 100-mL round-bottomed flask with a magnetic

stirbar. The flask was sealed with a three-way joint and evacuated to 60 mtorr and refilled

with high-purity nitrogen three times. DMF (15 mL) was then syringed into the flask and the

mixture stirred until homogeneous and then degassed repeatedly with freeze-pump-thaw

cycles. The flask was immersed in an oil bath at 120 oC for 5 h. After the polymerization, the

polymer was isolated via precipitation twice into methanol. 1H NMR (400 MHz,

DMSO-d6:CDCl3, 1:1, 25 °C) revealed block molecular weights 1.5K-16.5K-1.5K. The final

product was dried for 24 h under high vacuum at room temperature and stored in a dessicator.

The adenine triblock copolymer formed a clear, elastomeric polymer.

321

6.3.6 Characterization

Size exclusion chromatography (SEC) was performed at 40 °C in HPLC grade

tetrahydrofuran at 1 mL/min using a Waters size-exclusion chromatographer equipped with




standards. NMR spectroscopic data was collected on a Varian 400 MHz spectrometer at 25

°C. A Veeco MultiMode™ scanning probe microscope was used for tapping-mode AFM.

Polymer films were solution cast from chloroform on silicon. Samples were imaged at a

set-point ratio of 0.6-0.7. Veeco’s Nanosensor silicon tips having spring constants of 10-130

N/m were utilized for imaging. Solution rheology measurements were conducted on a TA

Instruments G2 Rheometer in concentric cylinder geometry. DSC was conducted on a TA

Instruments Q1000 DSC under nitrogen at a heating rate of 10 oC/min. X-ray data was

collected on an Oxford Diffraction XcaliburTM diffractometer equipped with a SapphireTM 3

CCD detector. The data collection routine, unit cell refinement, and data processing were

carried out with the program CrysAlis(v1.171, Oxford Diffraction: Wroclaw, Poland, 2004).

Small-angle X-ray Scattering (SAXS) Measurements. CuKα　　X-ray radiation was

generated using a Rigaku Ultrax18 rotating anode X-ray generator operated at 45 kV and 100

mA. A nickel filter was used to eliminate all wavelengths but the CuKα doublet, with an

average wavelength of λ = 1.542 Å. The exact beam center and the sample-to-detector

distance of approximately 1.5 m were calibrated using silver behenate. The 3 m camera

uses 3-pinhole collimation (300, 200 and 600 μm), and a sample-to-detector distance of

322

approximately 1.5 m. Two-dimensional data sets were collected using a Molecular

Metrology 2D multi-wire area detector. The data were corrected for detector noise, sample

absorption, and background scattering, followed by azimuthal averaging to obtain intensity as

a function of the scattering vector, I(q), where q = 4π·sin(θ)/λ and 2θ is the scattering angle.

The data were then placed on an absolute scale using a type 2 glassy carbon sample 1.07 mm

thick, previously calibrated at the Advanced Photon Source in the Argonne National

Laboratory, as a secondary standard. All data processing and analysis were done using

Wavemetrics IGOR Pro 5.04 software and IGOR procedures written by Dr. Jan Ilavsky of

Argonne National Laboratory.


6.4.1 Synthesis and Characterization of a Novel Difunctional Initiator

The difunctional alkoxyamine initiator, which is depicted as DEPN2 in Figure 6.2, was

synthesized from N-tert-butyl-N-(1-diethylphosphono-2,2-dimethylpropyl)-N-oxyl (DEPN)

and diethyl-2,5-dibromoadipate using conventional atom transfer radical addition

techniques.629630

- 631 The chemical structure of DEPN2, which consists of a mixture of

diastereomers, was confirmed using NMR spectroscopy and mass spectrometry, and the meso

629 Matyjaszewski, K.; Woodworth, B. E.; Zhang, X.; Gaynor, S.; Metzner, Z. Simple and Efficient Synthesis of Various Alkoxyamines for Stable Free Radical Polymerization. Macromolecules 1998, 31, 5955-7. 630 Lacroix-Desmazes, P.; Lutz, J. F.; Chauvin, F.; Severac, R.; Boutevin, B. Living Radical Polymerization: Use of an Excess of Nitroxide as a Rate Moderator. Macromolecules 2001, 34, 8866-71. 631 Diaz, T.; Fischer, A.; Jonquieres, A.; Brembilla, A.; Lochon, P. Controlled Polymerization of Functional Monomers and Synthesis of Block Copolymers Using a β-Phosphonylated Nitroxide. Macromolecules 2003, 36, 2235-41.

323

diastereomer was isolated in a crystalline form, which allowed structural determination using

X-ray crystallography (Figure 6.2).

In situ FTIR spectroscopy was used to probe the kinetics of DEPN2 initiated

homopolymerization of n-butyl acrylate. As expected for the difunctional initiator, the

polymerizations exhibited typical pseudo first-order kinetics and linear molecular weight

versus conversion profiles (Figure 6.3) with narrow molecular weight distributions (Mw/Mn ~

1.10). The difunctional nature of DEPN2 was demonstrated via polymerization of n-butyl

acrylate using mixtures of DEPN2 and a monofunctional alkoxyamine initiator

(Styryl-DEPN). Bimodal molecular weight distributions with a ratio of peak molecular

weights of 2:1 were observed, which was consistent with both monofunctional and

difunctional species.

324

Figure 6.2. ORTEP X-ray crystal structure of DEPN2 difunctional alkoxyamine initiator

(hydrogen atoms omitted for clarity).

H

HR SON

t-Bu

Pt-Bu O

EtO OEtH

S

EtO

O

ON

t-Bu

Pt-Bu

O

EtO OEt

H

R

OEt

O

325

Figure 6.3. Number average molecular weight as a function of monomer conversion for the

polymerization of n-butyl acrylate with DEPN2.

0

10000

20000

30000

40000

50000

60000

0 5 10 15 20

Conversion (%)

M

(g/m

ol)

In-situ FTIR H NMR1

n

326

6.4.2 Synthesis of Adenine Functional Block Copolymer

An adenine functionalized styrenic monomer, 9-vinylbenzyladenine (9-VBA), was

introduced after isolation of the telechelic DEPN functionalized poly(n-butyl acrylate)

(Figure 6.4). 1H NMR spectroscopy was used to verify the presence of the adenine containing

repeat units and allowed quantification of the degree of polymerization of the outer blocks.

Block molecular weights of 1.5K-16.5K-1.5K were calculated from 1H NMR data, assuming

an accurate SEC molecular weight for the rubber block (Mn = 16500). Size exclusion

chromatography (SEC) in tetrahydrofuran revealed a narrow molecular weight distribution

and monomodal traces for the final triblock copolymer, which was consistent with a

well-defined polymerization process. SEC was not suitable for the determination of hydrogen

bonding block molecular weights due to the relatively short block lengths. Thus, 1H NMR

was used to calculate the molecular weight for the shorter hydrogen bonding outer block.

327

Figure 6.4. Synthesis of adenine containing triblock copolymers from DEPN2 initiated

poly(n-butyl acrylate).

DMF120 oC

EtO

OEtO

O

OBuO

DEPN

O OBu

DEPNn nEtO

OEtO

O

OBuO

O OBu

n nDEPNDEPN

n n9-VBA

NN

NN

N N

H2N

NN

H2N

328

6.4.3 Compatible Blends of Adenine Functional Block Copolymer with Uracil

Phosphonium Salt

A novel uracil-containing phosphonium salt (UP+) was synthesized in a single step from

6-chloromethyl uracil and trioctylphosphine. UP+ exhibited an onset of weight loss at 280 ºC

using thermogravimetric analysis (TGA) as well as solubility in a wide range of common

organic solvents. In blends of the phosphonium salt with adenine containing block polymers

solution-cast from chloroform, crystallization and melting transitions of the phosphonium salt

were absent from differential scanning calorimetry (DSC) thermograms (Figure 6.5).

Furthermore, the solution-cast films were optically clear. In sharp contrast, solution-cast films

of the phosphonium salt with non-functionalized poly(n-butyl acrylate) homopolymer

resulted in opaque, macrophase separated, films.

329

Figure 6.5. DSC thermograms of adenine-containing block copolymer/UP+ blend (a) and UP+

(b). Heating rate 10 oC/min, 2nd heat, N2.

-0.5

0.0

Hea

t Flo

w (W

/g)

40 60 80 100 120 140 160 180 200Temperature (°C)Exo Up

-0.5

0.0

Hea

t Flo

w (W

/g)

-0.5

0.0

Hea

t Flo

w (W

/g)


-1.0

-0.5

0.0

0.5

1.0

Hea

t Flo

w (W

/g)


-1.0

-0.5

0.0

0.5

1.0

Hea

t Flo

w (W

/g)


a)

b)

330

6.4.4 Morphological Characterization of Phosphonium Salt Blends

Morphological investigations with atomic force microscopy (AFM) revealed unique

surface textures for the UP+ block copolymer blends compared with the pure adenine block

copolymer (Figure 6.6). Annealing at temperatures from 155 to 200 °C under vacuum or

nitrogen played a significant role in the surface morphology of the hydrogen bonding block

copolymers containing the phosphonium salt. Significant differences in terms of the

orientation of the domains relative to the surface were observed at each annealing

temperature. The morphology of the blends near the surface appeared to resemble a lamellar

morphology to a greater extent than the pure adenine containing block copolymer.

Corresponding SAXS data (Figure 6.7) revealed that the addition of the phosphonium salt

resulted in a shift in morphology from cylindrical to lamellar structures. The addition of one

equivalent of phosphonium salt corresponded with a change in hard phase from 15 to 37 wt%.

Transmission electron microscopy (Figure 6.8) of the phosphonium salt adenine polymer

blend further supported the assignment of a lamellar morphology and revealed similar

lamellar spacing (20 nm) compared to SAXS (15 nm). Reducing the concentration of the

phosphonium salt to less than stoichiometric levels (0.53 equiv) also resulted in a transition to

a lamellar morphology as determined through SAXS measurements.

331

Figure 6.6. Tapping mode AFM phase images of 1.5K-16.5K-1.5K adenine triblock UP+

blend (A:U 1:1) annealed at (a) 155 °C (b) 170 °C (c) 200 °C. (d) pure adenine triblock

copolymer annealed at 155 °C. Setpoint ratio = 0.6. All samples spin-coated on silicon and

annealed for 18 h under vacuum. Silicon surfaces were cleaned prior to spin-coating via

chloroform rinsing and drying with high-pressure nitrogen. Film thickness values were

approximately 100 nm.

250 nm250 nm250 nm 250 nm250 nm250 nm

250 nm250 nm250 nm 250 nm250 nm250 nm

332

0.001

0.01

0.1

1

10

0 0.05 0.1 0.15q (A-1)

Inte

nsity

Adenine polymer

Adenine polymer + UP

q*

√3q*

2q*

+

Figure 6.7. Small-angle X-ray scattering (SAXS) of 1.5K-16.5K-1.5K adenine triblock and

UP+ blend (A:U 1:1) annealed 155 °C for 18 h under vacuum.

333

Figure 6.8 Bright field TEM micrograph of adenine-containing polymer/UP+ blend stained

with OsO4.

334

6.4.5 Effect of Phosphonium Salt on Solution and Solid State Properties

Solution rheological studies of UP+ modified adenine containing triblock copolymers

were conducted in chloroform, which favors hydrogen bonding interactions due to a

relatively low dielectric constant. An apparent 3.4 fold decrease in solution viscosity of the

block copolymer solution (4.2 wt%, 25 °C) was observed upon the addition of one equivalent

UP+. This suggested a screening effect of the adenine-adenine self association between

polymer chains and further indicated the effectiveness of the hydrogen bonding interaction.

Dynamic mechanical (DMA) studies on the adenine polymer UP+ blends revealed that

the glass transition temperature of the rubber phase did not change significantly (Figure 6.9).

The rubber phase Tg of the blend was -32 ºC versus -29 ºC for the pure adenine polymer

according to the maximum of the loss modulus curve, indicating selective incorporation of

UP+ into the hard phase. Furthermore, the rubbery plateau modulus increased from 0.7 to

14.6 MPa at 25ºC, consistent with the increased hard phase volume fraction from 15 to 37

wt%. Interestingly, for the blend with UP+, the softening of the hard phase occurred at lower

temperatures (170 vs 230 ºC) again suggesting a screening effect of the adenine-adenine

intermolecular hydrogen bonds.

335

0.01

0.1

1

10

100

1000

10000

Sto

rage

Mod

ulus

(MP

a)

-100 -50 0 50 100 150 200 250Temperature ( C)

枛枛枛? Adenine polymer???? Adenine polymer + UP


Figure 6.9 Dynamic mechanical temperature sweep for pure 1.5K-16.5K-1.5K adenine triblock

copolymer and blend with 1 equivalent of UP+.

o

+

336

6.5 Conclusion

In conclusion, this manuscript defines a novel general strategy for the introduction of

thermally stable ionic sites to block copolymers via reversible complementary hydrogen

bonding. Novel adenine containing block copolymer precursors were synthesized using a

novel difunctional initiator. Subsequent blending with unique phosphonium cation

containing complementary hydrogen bonding guests was conducted. Influences on surface

morphology, solution viscosity, and mechanical properties were observed.

6.6 Acknowledgment

The authors would like to acknowledge Emily B. Anderson and Erika M. Borgerding

for electron microscopy. This material is based upon work supported by the U.S. Army

Research Laboratory and the U.S. Army Research Office under contract/grant number

DAAD19-02-1-0275 Macromolecular Architecture for Performance Multidisciplinary

University Research Initiative (MAP MURI).

337

Chapter 7. Novel Michael Addition Networks Containing

Poly(propylene glycol) Telechelic Oligomers

(Mather, B.D.; Miller, K.M.; Long, T.E. Macromolecular Chemistry and Physics 2006, 207,

1324-33.) Reproduced with permission, Copyright Wiley 2006.

7.1 Abstract

Poly(propylene glycol) oligomers with molecular weights ranging from 1000 to 8000

g/mol were end-functionalized with acetoacetate groups and subsequently crosslinking using

carbon-Michael addition with PEG diacrylate. Gel fraction analysis, dynamic mechanical

analysis (DMA), thermogravimetric analysis (TGA), tensile, and swelling measurements

were utilized to characterize the networks. The thermomechanical properties of the

networks were analyzed with respect to the molecular weight between crosslink points (Mc)

and the critical molecular weight for entanglement (Me). Sampling experiments during

crosslinking revealed the evolution of molecular weight with time and monomer conversion.

Kinetic analyses of the Michael additions were performed using 1H NMR spectroscopy, and

the influence of basic catalyst and concentration were elucidated.

338

7.2 Introduction

The Michael addition reaction has received significant attention as a versatile tool in the

synthesis of novel polymeric network structures.632633634635

-636637638639

640 The Michael addition reaction

offers mild conditions, functional group tolerance, and readily available precursors. More

recently, the carbon-Michael addition has demonstrated utility in the synthesis of polymeric

networks, which offer promise as high performance coatings, adhesives and laminates. The

carbon-Michael addition involves the reaction of enolate type nucleophiles such as

acetoacetate esters in the presence of base with α,β-unsaturated carbonyl compounds such as

acrylate esters. A wide range of basic catalysts are available for the synthesis of

carbon-Michael addition networks, including both organic (amidine) and inorganic

(hydroxide, carbonate) bases. The strength of the basic catalyst is critical in determining the

rate of the Michael addition due to the equilibrium for deprotonation of the acetoacetate ester.

632 Metters, A.; Hubbell, J. Network formation and degradation behavior of hydrogels formed by Michael-type addition reactions. Biomacromolecules 2005, 6, 290-301. 633 B.D. Mather, K. Viswanathan, K.M. Miller, T.E. Long Michael Addition Reactions in Macromolecular Design for Emerging Technologies. Prog. Polym. Sci. 2006, 31, 487-531. 634 Vernon, B.; Tirelli, N.; Bachi, T.; Haldimann, D.; Hubbell, J. Water-borne, in situ crosslinked biomaterials from phase-segregated precursors. J Biomed Mater Res 2003, 64A, 447-456. 635 Beckley, R.S.; Kauffman, T.F.; Zajaczkowski, M.J.; Whitman, D.W. Michael addition compositions. U.S. Pat. Appl., 2005245721, 2005. 636 Rizzi, S. C.; Hubbell, J. A. Recombinant protein-co-PEG networks as cell-adhesive and proteolytically degradable hydrogel matrixes. Part I: Development and physicochemical characteristics. Biomacromolecules 2005, 6, 1226-38. 637 van de Wetering, P.; Metters, A. T.; Schoenmakers, R. G.; Hubbell, J. A. Poly(ethylene glycol) hydrogels formed by conjugate addition with controllable swelling, degradation, and release of pharmaceutically active proteins. J Contr Rel 2005, 102, 619-27. 638 Clemens, R.J. Low temperature Michael addition reactions. U.S. Patent 5017649, 1991. 639 Moszner, N.; Rheinberger, V. Reaction behavior of monomeric β-ketoesters, 4) Polymer network formation by Michael reaction of multifunctional acetoacetates with multifunctional acrylates. Macromol Rapid Commun 1995, 16, 135-38. 640 Marsh, S. J. Acetoacetate chemistry- crosslinking versatility for high-solids coatings resins. Am Chem Soc, Div Polym Chem: Polym Prepr 2003, 44, 52-53.

339

Due to the presence of two acidic protons on the acetoacetate group, difunctionality of the

acetoacetate group is often observed.641 The acidities of the two acetoacetate protons differ

significantly (pKa1 ~ 12, pKa2 ~ 13), and this difference in reactivity leads to different

network structures depending on the strength of the basic catalyst.642 For, instance, Clemens

and Rector observed higher Michael bis-adduct formation for amidine bases compared to

more mono-adducts for inorganic bases.642 The Michael addition reaction provides

advantages over classical urethane bond forming reactions due to the elimination of highly

toxic isocyanates and also exhibits competitive rates compared to urethane formation,

allowing efficient curing at room temperature.

A wide range of hydroxyl functional telechelic oligomers are readily converted to

acetoacetate and acrylate functionality. In this work, hydroxyl terminated poly(propylene

glycol) (PPG) telechelic oligomers were functionalized with acetoacetate groups via a facile,

uncatalyzed transesterification with tert-butyl acetoacetate (tBAA). 643 These

bis(acetoacetate) precursors were subsequently crosslinked with PEG diacrylate (575 g/mol)

using the base catalyzed Michael addition (Figure 7.1). The ACCLAIM™ PPGs served as

ideal oligomeric precursors for this reaction due to near difunctionality of these oligomers,

which are prepared in the absence of base and do not possess allylic end groups. The

synthesis of networks via telechelic functionalized oligomers provides a convenient method

641 Kim, Y. B.; Kim, H. K.; Nishida, H.; Endo, T. Synthesis and characterization of hyperbranched poly(β-ketoester) by the Michael addition. Macromol Mater Eng 2004, 289, 923-6. 642 Clemens, R. J.; Rector, F. D. A comparison of catalysts for crosslinking acetoacetylated resins via the Michael reaction. J Coat Tech 1989, 61, 83-91. 643 Witzeman, J. S.; Nottingham, W. D. Transacetoacetylation with tert-butyl acetoacetate: synthetic applications. J Org Chem 1991, 56, 1713-8.

340

for creating model networks with controlled molecular weights between crosslink points.

The resulting model networks are considered more well-defined than typical sulfur or

peroxide vulcanized rubbers and often possess better mechanical properties due to the

presence of fewer dangling ends.644,645 Crosslinking telechelic oligomers to form model

networks was previously accomplished with polysiloxanes via hydrosilation of vinyl

terminated and SiH terminated oligomers,646647 648

-649 650 651

652 but other efforts involve telechelic

polyethers,653654

- 655 polyisobutylenes,656 polyurethanes,657 and polyimides.658

644 Mark, J.E. Some Interesting Things about Polysiloxanes. Acc Chem Res 2004, 37, 946-53. 645 Mark, J.E. New developments and directions in the area of elastomers and rubberlike elasticity. Macromol Symp 2003, 201, 77-84. 646 Batra, A.;Cohen, C.; Archer, L. Stress Relaxation of End-Linked Polydimethylsiloxane Elastomers with Long Pendent Chains. Macromolecules 2005, 38, 7174-80. 647 Meyers, K.O.; Bye, M.L.; Merrill, E.W. Model Silicone Elastomer Networks of High Juction Functionality: Synthesis, Tensile Behavior, Swelling Behavior, and Comparison with Molecular Theories of Rubber Elasticity. Macromolecules 1980, 13, 1045-53. 648 Urayama, K.; Miki, T.; Takigawa, T.; Kohjiya, S. Damping Elastomer Based on Model Irregular Networks of End-Linked Poly(Dimethylsiloxane). Chem Mater 2004, 16, 173-178. 649 Hedden, R. C.; Saxena, H.; Cohen, C. Mechanical Properties and Swelling Behavior of End-Linked Poly(diethylsiloxane) NetworksMacromolecules 2000, 33, 8676-84. 650 Kawamura, T.; Urayama, K.; Kohjiya, S. Multiaxial Deformations of End-Linked Poly(dimethylsiloxane) Networks. 1. Phenomenological Approach to Strain Energy Density Function. Macromolecules 2001, 34, 8252-60. 651 Braun, J. L.; Mark, J. E.; Eichinger, B. E. Formation of Poly(dimethylsiloxane) Gels. Macromolecules 2002, 35, 5273-82. 652 Shefer, A.; Gottlieb, M. Effect of crosslinks on the glass transition temperature of end-linked elastomers. Macromolecules 1992, 25, 4036-42. 653 Jong, L.; Stein, R. S. Synthesis, characterization, and rubber elasticity of end-linked poly(tetrahydrofuran) elastomer Macromolecules 1991, 24, 2323-29. 654 Lee, B. P.; Dalsin, J. L.; Messersmith, P. B. Synthesis and Gelation of DOPA-Modified Poly(ethylene glycol) Hydrogels. Biomacromolecules 2002, 3, 1038-47. 655 Andrady, A. L.; Sefcik, M. D. Glass transition in poly(propylene glycol) networks. J Polym Sci: Polym Phys Ed 1983, 21, 2453-63. 656 Lackey, J. E.; Chang, V. S. C.; Kennedy, J. P.; Zhang, Z. M.; Sung, P. H.; Mark, J. E. Polyisobutylene model elastomers prepared using demonstrably complete end-linking reactions. 2. Elongation moduli of the trifunctional networks prepared from the three-arm polymers. Polym Bull 1984, 11, 19-24. 657 Mark, J. E.; Sung, P. H. Chain extension studies relevant to the completeness of end-linking in elastomeric polyurethane networks. Rubber Chem Tech 1982, 55, 1464-8.

341

OHO H

n

O O

OtBu

OAcAcO AcAc

n

O O

O OOO

PPG

O

O PEG

O

O

DBUH H H H

O O

O OOOPPG

O

OO

OPEG

OO

O

OPEG

OO

OO

O O

O

O

PPG

NN

=

+

PPG PPG bisAcAc

Figure 7.1. Synthesis of acetoacetate networks from acetoacetate functionalized PPG (PPG

bisAcAc) using DBU as a basic catalyst.

658 Zhuang, H.; Sankarapandian, M. S.; Ji, Q.; McGrath, J. E. Thermosetting polyetherimides. The influence of reactive endgroup type and oligomer molecular weight on synthesis, network formation, adhesion strength, and thermal properties. J Adhesion 1999, 71, 231-62.

342

A range of PPGs of various molecular weights are available, allowing investigations of

the effect of the molecular weight between crosslink points relative to the critical molecular

weight for entanglement. The molecular weight between crosslink points (Mc) and crosslink

density are critical parameters in network synthesis, affecting such mechanical properties as

modulus, strength, and toughness as well as swelling.659660

- 661 Recent attention involves

studies of the effect of the molecular weight between crosslink points as a function of the

entanglement molecular weight (Me).662663

- 664 The entanglement molecular weight of PPG (Me

= 7700 g/mol)665 is in the range of commercially available ACCLAIM™ oligomers.

Furthermore, PPG is an atactic, amorphous polymer, which avoids the complexities of strain

induced crystallization that is typically observed in elastomers based on poly(tetramethylene

oxide) (PTMO) or poly(ε-caprolactone) (PCL).

A number of authors have examined the effect of entanglements on networks.666667

- 668 It

659 Mark, J. E. New developments and directions in the area of elastomers and rubberlike elasticity. Macromol Symp 2003, 201, 77-84. 660 Andrady, A. L.; Sefcik, M. D. Glass transition in poly(propylene glycol) networks. J Polym Sci: Polym Phys Ed 1983, 21, 2453-63. 661 Zhuang, H.; Sankarapandian, M. S.; Ji, Q.; McGrath, J. E. The influence of reactive endgroup type and oligomer molecular weight on synthesis, network formation, adhesion strength, and thermal properties. J Adhesion 1999, 71, 231-62. 662 Erman, B.; Mark, J. E., Structures and properties of rubberlike networks. Oxford University Press: New York, 1997. 663 Sung, P. H.; Pan, S. J.; Mark, J. E.; Chang, V. S. C.; Lackey, J. E.; Kennedy, J. P. Polyisobutylene model elastomers prepared using demonstrably complete end-linking reactions. 1. Elongation moduli of the trifunctional and tetrafunctional networks prepared from the linear polymers. Polym Bull 1983, 9, 375-81. 664 Bhawe, D. M.; Cohen, C.; Escobedo, F. A. Effect of chain stiffness and entanglements on the elastic behavior of end-linked elastomers. J Chem Phys 2005, 123, 014909-1/0124909/11. 665 Aharoni, S. M. On entanglements of flexible and rodlike polymers. Macromolecules 1983, 16, 1722-28. 666 Dossin, L. M.; Graessley, W. W. Rubber Elasticity of Well-Characterized Polybutadiene Networks. Macromolecules 1979, 12, 123-30.

343

is generally accepted that both crosslink points and entanglements, which are trapped during

curing, contribute to the elastic moduli of networks.669 Mazich and Samus have stated that

trapped entanglements, also known as topological constraints, can account for 20 to 90% of

the elastic modulus in networks. 670 The contribution to the elastic modulus from

entanglements increases as crosslink density decreases and the molecular weight between

crosslink points increases. Rubinstein and Panyukov recently developed a model which

separates contributions to the elastic modulus from classical phantom network crosslink

points and entanglements.671

The objective of this work was to study the effect of poly(propylene glycol) precursor

molecular weight on the mechanical properties of carbon-Michael addition networks in

relation to the critical molecular weight for entanglement. Additionally, the gelation process

was studied in relation to predictions from Flory’s theory. Efforts were also devoted to

studying the kinetics of the crosslinking reaction as a function of the basic catalyst employed.

7.3 Experimental

7.3.1 Materials

tert-Butyl acetoacetate (tBAA, 98%), poly(ethylene glycol) diacrylate (Mn = 575 g/mol),

667 Smedberg, A.; Hjertberg, T.; Gustafsson, B. The role of entanglements in network formation in unsaturated low density polyethylene. Polymer 2004, 45, 4867-75. 668 Hvidt, S., In Physical Networks: Polymers and Gels, Burchard, W.; Ross-Murphy, S. B., Eds. Elsevier: New York, 1988; pp 125-32. 669 Termonia, Y., In Synthesis, Characterization and Theory of Polymeric Networks and Gels, Aharoni, S. M., Ed. Plenum Press: New York, 1992; pp 201-207. 670 Mazich, K. A.; Samus, M. A. Role of entanglement couplings in threshold fracture of a rubber network. Macromolecules 1990, 23, 2478-83. 671 Rubinstein, M.; Panyukov, S. Elasticity of Polymer Networks. Macromolecules 2002, 35, 6670-86.

344

neopentyl glycol diacrylate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 98%),

tetramethylammonium hydroxide pentahydrate (TMAH) (97%) and

1,1,3,3-tetramethylguanidine (TMG, 99%), sodium methoxide (NaOMe, 25 wt% in methanol),

were purchased from Aldrich and used as received. Arcol™ poly(propylene glycol) diol

(1000 g/mol) (Bayer Co.), potassium tert-butoxide (KOtBu, 97%, TCI), and potassium

carbonate (99%, EM Science) were used as received. 2000, 4000, and 8000 g/mol

poly(propylene glycol) bis(acetoacetates) (PPG bisAcAc) were synthesized from

ACCLAIM™ poly(propylene glycol) diols using a method similar to the one described

below.

7.3.2 Synthesis of Acetoacetate Functionalized Poly(propylene glycol) (PPG bisAcAc)

Arcol™ poly(propylene glycol) (10.0 g, 10 mmol) and 6.3 g (40 mmol, 4 equiv) tBAA

were charged to a two-necked 100 mL flask, equipped with a short-path distillation head,

receiving flask, and magnetic stirbar. The mixture was maintained at 150 oC for 4 h and

gentle vacuum (100 mm Hg) was applied to remove the tert-butanol byproduct and excess

tBAA. An additional 6.3 g tBAA were added and heating continued for another 5 h at 150 oC

in order to ensure quantitative functionalization. Aspirator vacuum (~100 mmHg) and

finally high vacuum (0.1 mmHg) at 150 oC were applied to remove volatile starting reagents

and reaction byproducts. 1H NMR (400 MHz, CDCl3): δ = 1.12 ppm (br, PPG CH3), δ =

1.24 ppm (dd, 6H, CHCH3OAcAc), δ = 2.26 ppm (s, 6H, COCH2COCH3), δ = 3.4 ppm (br,

PPG CH), δ = 3.6 ppm (br, PPG CH2), δ = 5.08 ppm (m, 4H, CH2CHCH3OAcAc), δ = 5.29

ppm (s, enol C=CH-C=O), δ = 12.09 ppm (s, enol OH).

345

7.3.3 Crosslinking Reactions

2000 g/mol PPG bisAcAc (4.00 g, 2.00 mmol) and PEG diacrylate (1.60 g, 2.78 mmol,

1.40 equiv.) were mixed to form a homogeneous, clear, blend. DBU catalyst (50 mg, 1.25

wt% relative to PPG bisAcAc) was added and mixed thoroughly. The homogeneous

reaction mixture was transferred to a Teflon™ mold and cured at ambient temperature for 48

h. A dramatic increase in viscosity indicated that gelation occurred within minutes.

7.3.4 SEC and 1H NMR Analysis of the Crosslinking Process

4000 g/mol PPG bisAcAc (2.25 g, 0.563 mmol), PEG diacrylate (440 mg, 0.765 mmol,

1.40 equiv.) were mixed initially, and potassium carbonate (50% aq) catalyst (28 mg, 0.101

mmol, 0.16 equiv.) was added and mixed thoroughly. Samples (~ 100 mg) were

periodically removed from the crosslinking reaction prior to the gel point, rapidly quenched

with acidified THF (~10 mL + 1 drop 35 wt. % HCl) and immediately dried using rotary

evaporation and reduced pressure (0.1 mmHg) for 18 h at 25 oC. 1H NMR and SEC analysis

were used to determine PEG acrylate end group conversion and product molecular weight,

respectively.

7.3.5 1H NMR Kinetics Experiments

Kinetic analyses of the Michael addition reaction were performed using 1H NMR

spectroscopy. A stock reaction mixture of 2000 g/mol PPG bisAcAc (2.00 g, 1.00 mmol)

and PEG diacrylate (0.800 g, 1.39 mmol) was prepared, and 200 mg was added to each NMR

tube with 800 mg DMSO-d6. The 1H NMR spectra were collected upon addition of the

346

DBU catalyst (13.2 uL) with a microliter syringe. The tube was vigorously shaken prior to

insertion into the spectrometer. 1H NMR spectra were collected at regular intervals and the

conversion was reported as the ratio of the acrylate integration relative to the initial

integration, based on the PPG ether methylene and methyne (CH2 + CH, δ = 3.5 ppm)

resonances as an internal reference. In the case of overlapping catalyst resonances, the

acrylate integrations were referenced to the PPG methyl groups (δ = 1.1 ppm). The use of a

relatively high concentration of reagents allowed determination of conversion with 4 scans,

allowing measurements over ca. 30 seconds. Identical reactions external to the NMR

instrument were performed in parallel to determine gel points.


Size exclusion chromatography (SEC), was performed at 40 °C in THF at a flow rate of 1

mL/min using a Waters size exclusion chromatograph equipped with an autosampler, three 5

μm PLgel Mixed-C columns, a Waters 2410 refractive index (RI) detector operating at 880

nm, and a miniDAWN multiangle laser light scattering (MALLS) detector operating at 690

nm, which was calibrated with narrow polydispersity polystyrene standards. The refractive

index increment (dn/dc) was calculated online. 1H NMR spectroscopic data were collected

on a Varian 400 MHz spectrometer at ambient temperature. Gel fraction analysis was

performed using soxholet extraction in refluxing ethanol for 12 h followed by drying in a

vacuum oven for 18 h at 80 oC. Gel fractions were determined according to conventional,

gravimetric approaches.672 Dynamic mechanical measurements were conducted on a TA

672 Elzubair, A.; Suarez, J. C. M.; Bonelli, C. M. C.; Mano, E. B. Gel fraction measurements in gamma-irradiated ultra high molecular weight polyethylene. Polymer Testing 2003, 22, 647-9.

347

Instruments Q-800 DMA under nitrogen at a heating rate of 3 oC/min at 1 Hz frequency in

film tension mode. Tensile characterization was performed on an Instron model 4411 at

0.5”/min crosshead speed using miniature dogbone specimens and manual grips at ambient

conditions.


7.4.1 Synthesis of Acetoacetate Functionalized Poly(propylene glycol) (PPG bisAcAc)

The functionalization of PPG via transesterification with tBAA (Figure 7.1) is a more

facile route than previous techniques involving diketene or

2,2,6-trimethyl-4H-1,3-dioxin-4-one, which involve either noxious or difficult to synthesize

reagents, respectively.673 The relative ease of functionalization of alcohols with acetoacetate

groups enables the incorporation of numerous precursors into carbon-Michael addition

networks. In addition, the wide variety of acrylate functionalized molecules which are

commercially available or readily synthesized, further diversifies the Michael addition

networks. Simple vacuum distillation of excess tBAA starting material and tert-butanol

byproduct was the only necessary purification step.

A comparison of NMR based number average molecular weights of the PPG bisAcAcs

with the SEC molecular weights was performed. The ratio of the integrations of the AcAc

methyl resonances (δ = 2.26 ppm) with the PPG methyl resonances (δ = 1.12 ppm) was used

to calculate the NMR number average molecular weight. The comparison of molecular

673 Clemens, R. J.; Hyatt, J. A. Acetoacetylation with 2,2,6-trimethyl-4H-1,3-dioxin-4-one: A convenient alternative to diketene. J Org Chem 1985, 50, 2431-5.

348

weights from the different methods indicated nearly 100 % functionalization for the 1000 and

2000 g/mol PPG bisAcAc, however, lower levels of functionalization were observed for the

4000 and 8000 g/mol precursors (Table 7.1).

7.4.2 Synthesis of carbon-Michael Addition Networks

The acetoacetate functionalized PPGs of molecular weights ranging from 1000 to 8000

g/mol were successfully crosslinked via the Michael addition reaction with PEG diacrylate.

The gel times of the reaction mixtures increased with increasing PPG molecular weight, but

were generally less than 8 min in all cases (Figure 7.2). This was attributed to a lower

concentration of functional groups for higher molecular weight PPG oligomers. In order to

ensure high conversions at room temperature, 48 h cure times were employed, however, heat

(65oC) was also used for curing the 8000 g/mol PPG bisAcAc. The crosslinked networks

were optically clear, except for the 8000 g/mol PPG bisAcAc, which was translucent. The

difference for the 8000 g/mol PPG bisAcAc sample was attributed to the high molecular

weight of the PPG oligomer causing macrophase separation between the PPG and the PEG as

well as the lower functionality of the 8000 g/mol PPG bisAcAc precursor.

349

Table 7.1. Characterization of PPG bisAcAc precursors.

PPG bisAcAc Mn (g/mol)

(1H NMR) a

Mn (g/mol)

(SEC) b

Mw/Mn Degree of

functionalization c

(%)

1000 1300 1200 1.10 100

2000 2400 2400 1.05 100

4000 4300 4700 1.01 92

8000 10900 8300 1.02 76

a determined from the ratio of PPG CH3 (δ = 1.12 ppm) to AcAc CH3 (δ = 2.26 ppm)

b 40 oC, THF, MALLS

c ratio of SEC Mn to 1H NMR Mn

350

050

100150

200250

300350

400450

0 2000 4000 6000 8000 10000

PPG Mn (g/mol)

Gel

tim

e (s

)

Figure 7.2. Gel times for PPG bisAcAc / PEG diacrylate networks as a function of PPG

molecular weight.

351

Two different molar ratios of acrylate : acetoacetate were investigated in the preparation

of PPG bisAcAc / PEG diacrylate networks. Both a 2.0:1.0 (assumes acetoacetate f = 1) and

a 1.4:1.0 acrylate to acetoacetate molar ratio were used to synthesize carbon-Michael addition

networks. Both ratios lead to successful network synthesis. However, the 1.4:1.0 ratio

yielded higher tensile strengths, Young’s moduli, and lower swelling despite the assumption

of difunctionality of the acetoacetate group. These observations were consistent with less

than difunctionality for each acetoacetate, which is reasonable based on the higher pKa of the

second acetoacetate proton and greater steric hindrance of the second enolate anion.674

7.4.3 Characterization of the PPG bisAcAc / PEG diacrylate Networks

Gel fraction analysis was performed in order to assess the effectiveness of oligomer

incorporation into the network. Gel fraction analysis revealed a decrease in gel fraction

with increased PPG molecular weight (Table 7.2). For the 1.4:1.0 acrylate to acetoacetate

networks with 1.25 wt% DBU relative to PPG bisAcAc, a maximum gel fraction of 96% was

observed for the PPG 1000 g/mol oligomer. Higher molecular weight PPG bisAcAc

precursors lead to lower gel fractions. This result suggested the presence of dangling ends

and unincorporated sol, which were more significant for networks containing higher

molecular weight PPG bisAcAc precursors. In general, a slight decrease in the gel fraction

was observed with increased acrylate to acetoacetate ratios (2.0:1.0), with the exception of

the 2000 g/mol PPG bisAcAc, however these differences were generally close to the error of

the gel fraction measurement (± 5%). Incomplete reaction was proposed to account for the


352

low gel fractions of the higher molecular weight precursors, which is a potential consequence

of low end group concentration, mobility, and lower functionality of the high molecular

weight precursors. An alternate explanation presumed base catalyzed ester hydrolysis,

which is promoted in the presence of moisture in the networks, was more significant for

networks with lower crosslink densities. Networks were also synthesized using a lower

amount of catalyst (0.027 equiv. relative to AcAc groups) on the premise that less catalyst

would reduce the likelihood of ester hydrolysis. The use of lower catalyst levels resulted in

only slightly higher gel fractions (1-12%, Table 7.2). This was attributed to both slower cure

rates as well as decreased base catalyzed ester hydrolysis. Pavlinec and Moszner studied

networks based on PPG bisAcAc of low molecular weight (425 g/mol), crosslinked with

pentaerythritol tetraacrylate. 675 In their case, a stronger, basic catalyst,

1,5-diazabicylo[4.3.0]non-5-ene (DBN), was used at 2 mol% with a 2.0:1.0 acrylate to

acetoacetate stoichiometry. Gel fractions ranging from 59 to 94% were obtained, prompting

the use of photocrosslinking techniques to further consume acrylate groups and achieve

higher gel fractions.

675 Pavlinec, J.; Moszner, N. Photocured polymer networks based on multifunctional β-ketoesters and acrylates. J Polym Sci Part A: Polym Chem 1997, 10, 165-78.

353

Table 7.2. Gel fractions for PPG bisAcAc / PEG diacrylate networks.

PPG bisAcAc

Mn (g/mol)

1.4:1.0 Acrylate to

Acetoacetate

Gel fraction (%)

2.0:1.0 Acrylate to

Acetoacetate

Gel fraction (%)

Low catalyst*

1.4:1.0 Gel fraction

(%)

1000 96 88 97

2000 84 94 92

4000 85 81 88

8000 66 42 78

*0.027 equivalents of DBU catalyst relative to acetoacetate groups.

354

Dynamic mechanical analysis (DMA) was used to characterize the mechanical

properties of the PPG bisAcAc / PEG diacrylate networks with the 1.4:1.0 acrylate to

acetoacetate ratio (Figure 7.3). Increased rubbery plateau moduli were observed with a

decrease in PPG molecular weight. The plateau moduli for the two lowest PPG molecular

weights were nearly identical, contrary to expectations. The glass transition temperatures for

the networks, which were measured as the tan delta maxima, indicated increasing glass

transition temperature with decreasing PPG molecular weight. This result was expected

since higher crosslink densities further restrict chain motions. A linear dependence between

the glass transition temperature and inverse PPG bisAcAc molecular weight (Figure 7.4) was

observed, which is consistent with previous studies for other well-defined networks.676

676 Andrady, A.L.; Sefcik, M.D. Glass transition in poly(propylene glycol) networks. J Polym Sci: Polym Phys Ed 1983, 21, 2453-63.

355

Figure 7.3. Storage modulus (E’) plots for the PPG bisAcAc / PEG diacrylate networks

with a 1.4:1.0 acrylate to acetoacetate ratio.

1000 g/mol

2000 g/mol

4000 g/mol

8000 g/mol

356

R2 = 0.986

-50

-45

-40

-35

-30

-25

-20

0 0.0002 0.0004 0.0006 0.0008 0.001 0.0012

1/Mn PPG

Tg ºC

Figure 7.4. Glass transition temperatures of PPG bisAcAc / PEG diacrylate networks as a

function of inverse PPG molecular weight as determined by SEC (1.4:1.0 acrylate to

acetoacetate ratio).

357

Tensile measurements were performed on both the 1.4:1.0 and 2.0:1.0 acrylate to

acetoacetate crosslinked networks in order to probe the effect of PPG bisAcAc molecular

weight on the mechanical properties of the networks (Figure 7.5, Table 7.3). The 1000

g/mol, 2000 g/mol, and 4000 g/mol PPG bisAcAc networks exhibited low elongations

(<100%), and elongation increased with molecular weight. Concurrently, stress at break and

Young’s moduli decreased with increasing PPG molecular weight, due to decreasing

crosslink density. A marked change in properties was encountered for the 8000 g/mol PPG

network. The elongation of the network increased dramatically (~900%), and the moduli

and stress at break both dropped dramatically. This network was the only one consisting of

PPG segments with molecular weights above the entanglement molecular weight (Me = 7700

g/mol).677 The difference in mechanical performance compared to the lower molecular

weight PPG bisAcAc precursors could result from a combination of macrophase separation as

well as lower gel fraction for this network.

677 Aharoni, S. M. On entanglements of flexible and rodlike polymers. Macromolecules 1983, 16, 1722-28.

358

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0 100 200 300 400 500 600 700

Elongation (%)

Stre

ss (M

Pa)

Figure 7.5. Stress-strain curves for PPG bisAcAc / PEG diacrylate networks containing

1.4:1.0 acrylate to acetoacetate ratios. Measurement was performed at 25 oC.

359

Table 7.3. Tensile properties of PPG-bisAcAc/ PEG diacrylate networks.

1.4:1.0 Acrylate to Acetoacetate Networks

PPG Mn

(g/mol)

Stress at Break

(MPa)

Elongation

(%)

Young’s

Modulus

(MPa)

Toughness

(MPa)

1000 0.70 ± 0.05 21 ± 2 3.96 ± 0.43 0.078 ± 0.013

2000 0.48 ± 0.07 23 ± 4 2.71 ± 0.14 0.061 ± 0.019

4000 0.39 ± 0.03 50 ± 2 1.26 ± 0.15 0.109 ± 0.008

8000 0.065 ± 0.02 570 ± 54 0.022 ± 0.004 0.229 ± 0.088

2.0:1.0 Acrylate to Acetoacetate Networks

1000 0.48 ± 0.09 29 ± 6 2.11 ± 0.06 0.077 ± 0.029

2000 0.55 ± 0.07 51 ± 6 1.62 ± 0.07 0.158 ± 0.037

4000 0.44 ± 0.07 59 ± 10 1.20 ± 0.07 0.152 ± 0.049

8000 0.017 ± 0.006 920 ± 100 0.005 ± 0.002 0.109 ± 0.025

360

The molecular weight between crosslink points (Mc) is typically estimated from rubbery

elasticity theory, which describes the relationship between elastic modulus and crosslink

density.678 Assuming an affine network with tetrafunctional crosslink points and a Poisson’s

ratio of 0.5, Eq. 7.1 is defined as:

E = 3ρRT/Mc [7.1]

E = Young’s modulus (Pa) ρ = polymer density (g/cm3) R = gas constant (8.314 J/mol K) T = temperature (K)

The resulting values of Mc calculated from the Young’s moduli from tensile

experiments are shown in Table 7.4. The Mc values approximately corresponded to the PPG

bisAcAc precursor molecular weights for the lower molecular weight precursors (1000 and

2000 g/mol). The higher molecular weight sample (4000 g/mol) deviated significantly, and

the 8000 g/mol network produced values which were unreasonably high, likely a

consequence of the low gel fractions and macrophase separation for these networks. The Mc

values for the networks prepared with the 2.0:1.0 acrylate to acetoacetate ratio were

significantly higher than those obtained for the 1.4:1.0 ratio.

Swelling experiments were conducted on the networks in ethanol in order to further

investigate the effect of molecular weight of the PPG chains on crosslink density (Table 7.4).

As expected, the equilibrium solvent uptake increased with increasing PPG molecular weight.

The swelling was greater for the 2.0:1.0 acrylate to acetoacetate networks, in agreement with

678 Calvet, D.; Wong, J.Y.; Giasson, S. Rheological Monitoring of Polyacrylamide Gelation: Importance of Cross-Link Density and Temperature. Macromolecules 2004, 37, 7762-71.

361

the lower tensile strengths. Based on the theory of rubbery elasticity, the equilibrium

swelling of a network allows a calculation of the molecular weight between crosslink points,

Mc.679

Mc = -Vsρp(c1/3-0.5c)/(ln(1-c)+c+χc2) [7.2]

Vs = molar volume of solvent (cc/g) ρp = density of polymer (g/cc) χ = Flory Huggins polymer-solvent interaction parameter680 c = relative concentration of polymer (dimensionless) = (1+ρp(W-Wo)/ρsWo) ρs = density of solvent (g/cc) W = equilibrium weight of swollen sample (g) Wo = dry weight of sample (g)

In Eqn. 7.2 values of χ were utilized that reflected only poly(propylene glycol) which

represented the majority of the networks.680 The values of Mc obtained from swelling data

increased with PPG bisAcAc molecular weight but slightly differed from those obtained from

tensile measurements. The Mc values obtained from both swelling and modulus

measurements were consistent or greater than the precursor molecular weight, suggesting the

absence of significant entanglements.

679 Pavlinec, J.; Moszner, N. Photocured polymer networks based on multifunctional β-ketoesters and acrylates. J Polym Sci Part A: Polym Chem 1997, 10, 165-78. 680 Conway, B.E.; Nicholson, J.P. Some experimental studies on enthalpy and entropy effects in equilibrium swelling of poly(oxypropylene) elastomers. Polymer 1964, 5, 387-402.

362

Table 7.4. Swelling properties of PPG bisAcAc / PEG diacrylate networks in ethanol and Mc

values calculated from both swelling and tensile data.

1.4 : 1.0 Acrylate to Acetoacetate 2.0:1.0 Acrylate to Acetoacetate

PPG Mn

(g/mol)

Equilibrium

Swelling

(wt%)

Mc

Swelling

(g/mol)

Mc

Tensile

(g/mol)

Equilibrium

Swelling

(wt%)

Mc

Swelling

(g/mol)

Mc

Tensile

(g/mol)

1000 103 ± 1.5 1000 1900 136 ± 1.3 1500 3500

2000 180 ± 0.8 2800 2760 215 ± 1.6 3900 4600

4000 320 ± 1.3 8000 5900 293 ± 3.3 6800 6200

8000 1140 ± 38 77000 340000 1036 ± 273 76000 1.5E6

363

7.4.4 Sampling Experiments of the Crosslinking Reaction Involving SEC Analysis

Sampling experiments were pursued in order to study the progress of molecular weight

and molecular weight distribution during crosslinking. Crosslinking reactions were

performed using the 4000 g/mol PPG bisAcAc and PEG diacrylate. Samples were removed

at regular intervals and subjected to SEC and 1H NMR spectroscopic analysis which allowed

measurement of both molecular weight and acrylate conversion. The broadening in the

molecular weight distribution is clearly evident in the early stages of the reaction (Figure 7.6),

and after only 3 min, multimodality is evident. The complexity of the SEC traces indicated

that numerous species were present in the reaction mixture. The evolution of molecular

weight (from both multi-angle laser light scattering (MALLS) and refractive index (RI)

detectors) with diacrylate conversion is shown in Figure 7.7. The marked upturn in

molecular weight near the gel point is typical of step growth crosslinking, where incremental

conversion results in rapidly increasing molecular weight. The observed gel point occurred

at 13 min, shortly after the last sample was removed. Flory developed a theory of gelation

describing the critical conversion to reach the gel point (Eq. 4.3).681,682

[ ] 2/1)2(1

−+=

frrpc ρ

[4.3]

pc = conversion of multifunctional (AcAc) groups at the gel point r = ratio of multifunctional (AcAc) to difunctional groups (acrylate) = 0.71 ρ = fraction of AcAc groups present on multifunctional unit = 1.0 f = functionality of the branch point = 4 (assumed)

For the acrylate to acetoacetate ratio of 1.4:1.0, the theoretical gel point occurs at 68 %

681 Flory, P.J. Molecular Size Distribution in Three Dimensional Polymers. I. Gelation. J Am Chem Soc 1941, 63, 3083-90. 682 Chanda, M. "Advanced Polymer Chemistry", Marcel Dekker, New York, 2000.

364

acrylate conversion. Although the conversion at the gel point was not known, the acrylate

conversion of the last sample (70%) is consistent with theoretical predictions.

365

Figure 7.6. SEC traces from a PPG bisAcAc / PEG diacrylate crosslinking reaction.

Minutes

14.00 15.00 16.00 17.00 18.00 19.00 20.00 21.00 22.00 23.00 24.00

Minutes

14.00 15.00 16.00 17.00 18.00 19.00 20.00 21.00 22.00 23.00 24.00

Minutes

14.00 15.00 16.00 17.00 18.00 19.00 20.00 21.00 22.00 23.00 24.00

0 min

3.8 min

7.8 min

10 min

11.1 min

11.6 min

366

0

10000

20000

30000

40000

50000

60000

70000

80000

0 20 40 60 80

Acrylate Conversion (%)

Mol

ecul

ar w

eigh

t (g/

mol

) . MALLS Mw

RI Mw

Figure 7.7. Weight-average molecular weight as determined by SEC MALLS and refractive

index versus acrylate conversion determined by 1H NMR spectroscopy. The experimental

acrylate conversion slightly exceeds the theoretical value (vertical dashed line).

367

7.4.5 Kinetic Investigations of the carbon-Michael Addition Crosslinking Reaction

The kinetics of the base catalyzed Michael reaction are highly dependent on the base

strength and concentration. 683 Under the conditions of the present experiments, the

consumption of acrylate groups follows pseudo first-order kinetics due to the fact that an

equilibrium concentration of enolate ion is rapidly established, leading to the lack of

dependence on acetoacetate concentration.684 The presence of a second labile acetoacetate

proton leads to complexities in the kinetics at higher conversions. Kinetic investigations of

the carbon-Michael addition reactions were pursued using 1H NMR spectroscopy, which was

effective in quantifying the conversion of acrylate groups. A simple first-order rate plot

confirmed the first-order kinetics for the PPG bisAcAc / PEG diacrylate crosslinking reaction

in DMSO-d6 using DBU as a basic catalyst (Figure 7.8) at 25 oC.

Numerous basic catalysts are effective in the carbon-Michael addition reaction,

including both homogeneous and heterogeneous organic and inorganic bases.683 An

effective basic catalyst for the carbon-Michael addition possesses a pKa of the conjugate acid

near or above the pKa of the abstractable protons of the acetoacetate group (pKa1 ~ 12, pKa2~

13) (Table 7.5). Organic bases such as TMG and DBU, soluble inorganic bases such as

tetramethylammonium hydroxide (TMAH) and sodium methoxide, and heterogeneous

inorganic bases such as potassium tert-butoxide and potassium carbonate were investigated.

TMAH provided the highest reaction rate and exhibited an observed pseudo-first-order rate

683 Mather, B.D.; Viswanathan, K.; Miller, K.M.; Long, T.E. Michael Addition Reactions in Macromolecular Design for Emerging Technologies. Prog. Polym. Sci. 2006, 31, 487-531. 684 Clemens, R. J.; Rector, F. D. A comparison of catalysts for crosslinking acetoacetylated resins via the Michael reaction. J Coat Tech 1989, 61, 83-91.

368

constant of kobs = 4.9 x 10-3 s-1. Interestingly, this strong hydroxide base did not lead to gel

formation despite the high rate constant. This is likely due to nucleophilic attack and

hydrolysis of the ester bonds contained in the precursors. Reducing the concentration of

TMAH resulted in slower acrylate consumption but permitted gelation to occur after 13 min.

The amidine bases DBU and TMG exhibited the next highest rate constants and also

produced gels easily, likely due to their lack of nucleophilicity. The inorganic base sodium

methoxide had a surprisingly low rate constant despite its complete solubility in reaction

medium and relatively high basicity. The weak base potassium carbonate exhibited the

lowest rate constant, but produced gel in 36 min. The activity of potassium carbonate was

surprising due to its low pKa, which is about 2 units below the pKa of the acetoacetate protons.

For the organic bases DBU and TMG, the acrylate conversion at the gel point was similar to

the theoretical conversion. However, for the inorganic bases KOtBu and K2CO3, higher

conversion was needed to reach the gel point, presumably due to ester hydrolysis or

preferential mono-adduct formation, which Clemens and Rector have reported earlier for

alkoxide bases.685


369

y = 0.0032x + 0.0826

0

0.5

1

1.5

2

2.5

0 200 400 600 800

time (s)

-ln [A

]/[A

] o

Figure 7.8. First-order rate analysis of acrylate concentration [A] from 1H NMR spectroscopy

for a PPG bisAcAc / PEG diacrylate crosslinking experiment in DMSO-d6 using DBU as a

basic catalyst.

370

Table 7.5. Kinetic data for the PPG bisAcAc / PEG diacrylate reaction using various basic

catalysts. The pKa data is in aqueous solution.

Catalyst Homogeneous Gel time

(min)

kobs (s-1) x

10-3

pKa conj.

acid*

Pacryl at

gel point*

TMAH Y - 4.9 14 -

DBU Y 5 4.7 12.5 78%

TMG Y 6 3.2 13.6 73%

NaOMe Y - 1.2 15.5 -

K2CO3 N 36 0.92 10.3 86%

KOtBu N 12.5 2.8 19.2 92%

*Conversion of acrylate groups at the gel point

371

7.5 Conclusions

Networks based on PPG bisAcAc oligomers with a range of molecular weights were

synthesized and characterized via mechanical testing, swelling, and gel fraction analysis.

The gel fractions appeared to decrease with increasing oligomer molecular weight, and were

markedly lower for the 8000 g/mol PPG bisAcAc precursor. This was attributed to

incomplete reaction, macrophase separation, and lower functionality for this precursor. As

expected, the glass transition temperature, tensile elongation and swelling ratio increased

with the precursor oligomer molecular weight whereas the Young’s modulus and tensile

strengths decreased. Swelling and tensile measurements allowed calculation of the

molecular weight between crosslink points (Mc). Mc values increased with precursor

molecular weight but were greater than the precursor molecular weights, suggesting the

absence of significant numbers of trapped entanglements in these networks. Sampling

experiments involving SEC and 1H NMR spectroscopy showed a rapid increase in molecular

weight with time (or conversion) near the gel point and the measured conversion near the gel

point was close to theoretical predictions. Kinetics experiments conducted using 1H NMR

spectroscopy demonstrated pseudo first-order kinetics and established reaction rates for a

range of basic catalysts.


The authors would like to acknowledge the financial support of Rohm and Haas

Company and the Department of Energy (DE-FG36-04GO14317).

372

Chapter 8. Synthesis of an Acid-Labile Diacrylate Crosslinker for

Cleavable Michael Addition Networks

(Mather, B.D.; Williams, S.R.; Long, T.E. Macromol. Chem. Phys., submitted)

8.1 Abstract

A novel acid-cleavable diacrylate crosslinker, dicumyl alcohol diacrylate (DCDA), was

synthesized. DCDA was utilized as a difunctional Michael acceptor in the synthesis of

acid-cleavable crosslinked networks via base-catalyzed Michael addition of telechelic

poly(ethylene glycol) bis(acetoacetate). The hydrophilic networks that were chemically

stable at ambient conditions had a rubbery plateau storage modulus of 1.2 MPa. Michael

addition networks containing DCDA were degraded in the presence of catalytic quantities of

acids such as trifluoroacetic acid (TFA), p-toluenesulfonic acid, and HCl to form completely

soluble polymeric products. Michael addition networks composed of non-degradable

diacrylate crosslinkers were chemically unchanged under identical reaction conditions and

remained insoluble. Thermal degradation of DCDA containing networks was also

investigated using thermogravimetric analysis (TGA), which confirmed the thermal reactivity

and concentration of the acid-labile crosslink points.

8.2 Introduction

Acid-cleavable esters such as tert-butoxy carbonyl (t-BOC) esters and their derivatives

have found widespread application in organic synthesis as protecting groups for nucleophilic

373

functional groups such as alcohols, phenols, amines, and thiols. 686 These esters are

quantitatively cleaved in the presence of catalytic quantities of acids such as trifluoroacetic

acid (TFA)687 or p-toluene sulfonic acid.688 They are also readily cleaved with certain

transition metals such as cerium ammonium nitrate, 689 and may also be thermally

deprotected.690 Acid-cleavable esters serve integral roles in peptide synthesis,687,691 and

photoresists690, 692693

- 694 in semiconductor technology. In the case of photoresists, a

photo-acid generator (PAG) is blended with a t-BOC protected polymer. Exposure to

ultraviolet light triggers acid production which cleaves the t-BOC group, resulting in a

solubility change in the polymer.695 Due to the catalytic activity of the acid, the term

686 Greene, T. Protective groups in organic synthesis. 3rd ed.; Wiley: New York, 1999. 687 Pellois, J.P.; Wang, W.; Gao, X. Peptide Synthesis Based on t-Boc Chemistry and Solution Photogenerated Acids J. Comb. Chem. 2000, 2, 355-60. 688 Reginato, G.; Mordini, A.; Caracciolo, M. Synthetic Elaboration of the Side Chain of (R)-2,2-Dimethyl-3-(tert-butoxycarbonyl)-4-ethynyloxazolidine: A New Regio- and Stereoselective Strategy to -Functionalized -Amino Alcohols. J. Org. Chem. 1997, 62, 6187-92. 689 Hwu, J.-R.; Jain, M.; Tsay, S.-C.; Hakimelahi, G. Ceric ammonium nitrate in the deprotection of tert-butoxycarbonyl group. Tetrahedron Letters 1996, 37, 2035-8. 690 Ahn, K.-D.; Koo, D.-I.; Willson, C. Synthesis and polymerization of t-BOC protected maleimide monomers: N-(t-butyloxycarbonyloxy)maleimide and N-[p-(t-butyloxycarbonyloxy)phenyl]-maleimide Polymer 1995, 36, 2621-8. 691 Merrifield, R.B. Solid Phase Peptide Synthesis. II. The Synthesis of Bradykinin. J Am Chem Soc 1964, 86, 304-5. 692 Yoo, J.-H.; Kim, S.-Y.; Cho, I.; Kim, J.-M.; Ahn, K.-D.; Lee, J.-H. A single component photoimaging system with styrene copolymers having t-BOC-protected quinizarin dye precursors and photoacid generating groups in a single polymer chain. Polymer 2004, 45, 5391-5. 693 Fréchet, J.M.J; Eichler, E.; Ito, H.; Willson, C.G. Poly(p-t-butoxycarbonyloxystyrene): A Convenient Precursor to p-Hydroxystyrene Resins. Polymer 1983, 24, 995-1000. 694 Chang, S.Q.; Ayothi, R.; Bratton, D.; Yang, D.; Felix, N.; Cao, H.B.; Deng, H.; Ober, C.K. Sub-50 nm feature sizes using positive tone molecular glass resists for EUV lithography. J Mater Chem 2006, 16, 1470-4. 695 Gabor, A. H.; Pruette, L. C.; Ober, C. K. Lithographic Properties of Poly(tert-butyl methacrylate)-Based Block and Random Copolymer Resists Designed for 193 nm Wavelength Exposure Tools. Chem Mater 1996, 8, 2282-90.

374

chemically amplified resist,696 was adopted.

The Michael addition reaction, which involves the addition of nucleophiles to activated

olefins, has generated recent interest in polymer synthesis.697 Michael addition chemistry is

particularly suited for the synthesis of networks, due to the ability for room temperature

curing and a wide range of functional crosslinkable oligomeric precursors. The Michael

addition reaction enables applications in the synthesis of high-performance crosslinked

resins,698 durable coatings699 and biodegradable hydrogels.700 The Michael addition is often

employed in network synthesis and involves the reaction of acetoacetate functionalized

precursors,701 which are easily derived from hydroxyl containing precursors through a facile,

uncatalyzed transesterification with tert-butylacetoacetate.702

In this manuscript, we report the synthesis of Michael addition networks containing a

novel acid-cleavable diacrylate crosslinker, dicumyl alcohol diacrylate (DCDA). These

networks benefit from facile room temperature curing and possess the unique property of

being degradable in the presence of strong acids. The tertiary esters in DCDA cleave under

696 Fréchet, J. M. J.; Eichler, E.; Ito, H.; Willson, C. G. Poly(p-t-butoxycarbonyloxystyrene): A Convenient Precursor to p-Hydroxystyrene Resins. Polymer 1983, 24, 995-1000. 697 Mather, B. D.; Viswanathan, K.; Miller, K. M.; Long, T.E. Michael Addition Reactions in Macromolecular Design for Emerging Technologies. Prog. Polym. Sci. 2006, 31, 487-531. 698 Curliss, D. B.; Cowans, B. A.; Caruthers, J. M. Cure reaction pathways of bismaleimide polymers: a solid-state 15N NMR investigation. Macromolecules 1998, 31, 6776-82. 699 Clemens, R. J.; Rector, F. D. A comparison of catalysts for crosslinking acetoacetylated resins via the Michael reaction. J Coat Tech 1989, 61, 83-91. 700 Metters, A.; Hubbell, J. Network formation and degradation behavior of hydrogels formed by Michael-type addition reactions. Biomacromolecules 2005, 6, 290-301. 701 Clemens, R. J.; Hyatt, J. A. Acetoacetylation with 2,2,6-trimethyl-4H-1,3-dioxin-4-one: A convenient alternative to diketene. J Org Chem 1985, 50, 2431-5. 702 Witzeman, J. S.; Nottingham, W. D. Transacetoacetylation with tert-butyl acetoacetate: synthetic applications. J Org Chem 1991, 56, 1713-8.

375

mild acidic conditions through a cationic mechanism to generate a diene by-product as well

as polymer-bound carboxylic acid functionalities.

Previous work in our research laboratories has demonstrated the utility of

acid-cleavable dimethacrylates in the synthesis of core-cleavable star polymers synthesized

via anionic polymerization.703 Others have also reported the utility of acid-labile linkers in

polymer science. For instance, Patrickios et al. have synthesized novel asymmetric aliphatic

tertiary ester containing dimethacrylates and generated networks as well as star polymers via

group transfer polymerization, which were hydrolyzable in the presence of TFA.704 Size

exclusion chromatography (SEC) measurements over time were used to monitor the

decomposition of core-cleavable star polymers into component arms. Ober et al. utilized

aliphatic ditertiary ester-containing dimethacrylates and diacrylates to synthesize thermally

degradable photocured networks.705 Decomposition of the networks via thermal treatment

led to poly(acrylic acid) derivatives which were soluble in aqueous base.

Acid-cleavable networks may offer potential applications as drug delivery devices, and

in particular, delivery of drugs to cancerous tumors, which relies on the lower pH within the

surrounding tissue.706 Biodegradable Michael addition networks have been synthesized for

703 Kilian, L.; Wang, Z.-H.; Long, T. E. Synthesis and Cleavage of Core-Labile Poly(Alkyl Methacrylate) Star Polymers. J Polym Sci: Part A: Polym Chem 2003, 41, 3083-93. 704 Kafouris, D.; Themistou, E.; Patrickios, C. Synthesis and Characterization of Star Polymers and Cross-Linked Star Polymer Model Networks with Cores Based on an Asymmetric, Hydrolyzable Dimethacrylate Cross-Linker. Chem Mater 2006, 18, 85-93. 705 Ogino, K.; Chen, J.-S.; Ober, C. Synthesis and Characterization of Thermally Degradable Polymer Networks. Chem Mater 1998, 10, 3833-8. 706 Murthy, N.; Thng, Y.; Schuck, S.; Xu, M.; Frechet, J. A Novel Strategy for Encapsulation and Release of Proteins: Hydrogels and Microgels with Acid-Labile Acetal Cross-Linkers. J Am Chem Soc 2002, 124, 12398-9.

376

drug delivery applications,707 and acid-degradable networks have potential applications in

tissue scaffolds. Hubbell et al. has synthesized biodegradable tissue scaffolds708 and tissue

reinforcements709 using the Michael addition.

Applications of acid-cleavable networks in photolithography were studied by Reiser et

al. with networks made from 2,5-dimethyl-2,5-hexanediol dimethacrylate.710 It was found

that partial cleavage of crosslink points resulted in local changes in tack, which allowed the

adhesion of toner and circumvented solvent-based development. Fréchet and Willson also

utilized acid-sensitive acetal linkages to develop novel acid-cleavable networks for

photoresist technology.711 Fréchet applied this same acetal chemistry to create protein

delivery devices which operate under acidic conditions such as those found in cancerous

tissue.712 Rapid protein release at pH 5.0 was observed with these highly sensitive acetal

linked networks.

707 Elbert, D.; Pratt, A.; Lutolf, M.; Halstenberg, S.; Hubbell, J. Protein delivery from materials formed by self-selective conjugate addition reactions. J Control Release 2001, 76, 11–25. 708 Elbert, D.; Hubbell, J. Conjugate addition reactions combined with free-radical cross-linking for the design of materials for tissue engineering. Biomacromolecules 2001, 2, 430-41. 709 Vernon, B.; Tirelli, N.; Bachi, T.; Haldimann, D.; Hubbell, J. A. J Biomed Mater Res 2003, 64A, 447-56. 710 Li, M. Y.; Liang, R. C.; Raymond, F.; Reiser, A. J Imaging Sci 1990, 34, 259-64. 711 Yamada, S.; Medeiros, D.; Patterson, K.; Jen, W.-L.; Rager, T.; Lin, Q.; Lenci, C.; Byers, J.; Havard, J.; Pasini, D.; Frechet, J.; Willson, C. Positive and negative tone water processable photoresists: a progress report. SPIE Proc: Advances in resist technology and processing 1998, 3333, 245-53. 712 Murthy, N.; Thng, Y.; Schuck, S.; Xu, M.; Frechet, J. A Novel Strategy for Encapsulation and Release of Proteins: Hydrogels and Microgels with Acid-Labile Acetal Cross-Linkers. J Am Chem Soc 2002, 124, 12398-9.

377

8.3 Experimental

8.3.1 Materials

α,α,α',α'-tetramethyl-1,4-benzenedimethanol (99%), tert-butylacetoacetate (98%),

p-toluene sulfonic acid monohydrate (98%), trifluoroacetic acid (99%),

1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 98%) and 1,1,3,3-tetramethylguanidine (TMG,

99%) were purchased from Aldrich and used as received. Acryloyl chloride (96%) and

triethylamine (99.5%) were purchased from Aldrich and distilled prior to use.

Tetrahydrofuran was distilled from sodium and benzophenone under nitrogen prior to use.

Poly(ethylene glycol) (Mn = 600 g/mol) was used as received. Poly(propylene glycol)

bis(acetoacetate) (Mn = 1000 g/mol) was synthesized according to previously reported

procedures.713

8.3.2 Dicumyl alcohol diacrylate (DCDA)

α,α,α',α'-tetramethyl-1,4-benzenedimethanol (6.25 g, 32.2 mmol) was dissolved in 100

mL dry tetrahydrofuran in a 500 mL round-bottomed flask containing a magnetic stirbar.

Triethylamine (10.7 mL, 76.8 mmol, 2.38 equiv) were added via syringe. The flask was

equipped with an addition funnel and 50 mL of dry THF were added to the funnel. Acryloyl

chloride (5.70 mL, 74.9 mmol, 2.32 equiv) were syringed into the addition funnel. The

reaction flask was cooled with an ice bath and the acid chloride was added dropwise to the

reaction and the reaction was allowed to warm to room temperature. Stirring was continued

713 Mather, B. D.; Miller, K. M.; Long, T. E. Novel Michael Addition Networks Containing Poly(propylene glycol) Telechelic Oligomers. Macromol Chem Phys 2006, 207, 1324-33.

378

for 18 h. The triethylamine salt was filtered off and the reaction mixture was evaporated. The

crude product was chromatographed on silica using chloroform eluent. The final product was

obtained in 28% yield and was stored at -15 oC. 1H NMR, CDCl3 (δ, ppm): 7.33 (s, 4H), 6.34

(dd, 2H, J1 = 17.4 Hz, J2 = 1.6 Hz), 6.11 (dd, 2H, J1 = 10.4, J2 = 17.5 Hz), 5.77 (dd, 2H, J1 =

10.3 Hz, J2 = 1.6 Hz) 1.81 (s, 12H). 13C NMR (δ, ppm): 28.51, 81.74, 124.19, 129.77, 129.96,

144.17, 164.81 ppm. FAB MS: m/z = 302.151 [M]+, m/z = 302.15 (theoretical)

8.3.3 Poly(ethylene glycol) bis(acetoacetate)

Poly(ethylene glycol) (Mn = 600 g/mol) (3.0 g, 5.0 mmol) and tert-butyl acetoacetate

(2.0 g, 12.6 mmol) were combined in a 50 mL round-bottomed flask containing a magnetic

stirbar. The flask was heated under nitrogen at 150 oC for 2 h. A short-path condenser was

adapted to the flask and vacuum from an aspirator was applied to remove tert-butanol

byproduct. The condenser was removed and an additional of aliquot of tert-butyl acetoacetate

(2.0 g, 12.6 mmol) were added and the reaction was continued for another 1.5 h. Aspirator

vacuum was applied a second time followed by high vacuum to remove excess reagents and

byproducts. 1H NMR was used to verify the presence of the acetoacetate end groups. 1H

NMR, CDCl3 (δ, ppm): 5.01 (s, enol vinyl H), 4.28 (t, 4H, J = 4.4 Hz), 3.69 (t, 4H, J = 4.8

Hz), 3.62 (s, PEG CH2), 3.46 (s, 4H), 2.25 (s, 6H).

8.3.4 Crosslinked Network Synthesis and Degradation

DCDA (152 mg, 0.50 mmol) was mixed with poly(ethylene glycol) bis(acetoacetate)

(149 mg, 0.25 mmol) at room temperature for 2 min. DBU (3 uL, 0.020 mmol) and TMG (5

379

uL, 0.040 mmol) were added and mixed with the blend of crosslinkable precursors, resulting

in an amber color due to the enolate anion formation. The blend gelled over a period of

several hours. A sample of DCDA-poly(ethylene glycol) bis(acetoacetate) containing network

(5 mg) was placed in dioxane (3.0 g) in a 20 mL sample vial containing a magnetic stirbar

and p-toluenesulfonic acid (300 mg) was added. The sample degraded in 30 min into a

homogeneous solution. The DCDA containing networks were also degraded in trifluoroacetic

acid (TFA) solution. The DCDA containing Michael addition network (32 mg) was

introduced to a solution of TFA in dichloromethane (20 vol%) and stirred at 25 oC. The

network degraded in 50 s into a completely homogeneous solution. The network was also

successfully degraded in concentrated HCl (35 wt%) into small, insoluble particles was

achieved in 3 min at room temperature.


1H NMR was conducted using a Varian Inova 400 MHz spectrometer. Gel fraction

analysis was conducted by immersing the samples in ethanol for 5 d, changing the ethanol

every 24 h. Samples were dried after extraction in vacuum at 50 oC for 18 h and reweighed to

obtain the gel content. Fast atom bombardment (FAB) mass spectrometry was conducted

using a JEOL HX-110 dual focusing mass spectrometer in positive ion mode with xenon ion

bombardment and a matrix of 3-nitrobenzyl alcohol with polyethylene glycol standards.

Thermogravimetric analysis (TGA) was performed under a nitrogen atmosphere at a heating

rate of 10 °C/min using a TA Instruments Hi-Res TGA 2950. Dynamic mechanical

measurements were conducted on a TA Instruments Q-800 DMA under nitrogen at a heating

380

rate of 3 oC/min at 1 Hz frequency in film-tension mode. Tensile characterization was

performed on an Instron model 5500R at 100%/min elongation using rectangular specimens

and manual grips at ambient conditions.


8.4.1 Synthesis of Acid-Cleavable Networks

The acid-cleavable diacrylate crosslinker, DCDA, was synthesized in a single step from

acryloyl chloride and α,α,α',α'-tetramethyl-1,4-benzenedimethanol. The product oil was

isolated through column chromatography and remained stable at -15 oC. Multinuclear NMR

spectroscopy (Figure 8.1) and mass spectrometry were used to confirm the structure of the

product. The diacrylate crosslinker maintained solubility in a range of solvents, potentially

allowing miscibility and network formation with Michael addition donors of varying polarity.

The Michael addition networks were synthesized through blending the DCDA crosslinker

with a poly(ethylene glycol) bis(acetoacetate) (Mn = 600 g/mol) and adding base catalysts,

such as DBU and TMG (Figure 8.2). This resulted in rapid gelation at 25 oC in air. The gel

content of the network was determined through removal of sol through immersion in ethanol,

which is a solvent known to dissolve the network precursors, for a period of 5 d, with daily

replacement of the solvent. The gel content of the Michael addition networks were typically

89±2%.

381

Figure 8.1. 1H NMR spectrum of acid-cleavable diacrylate crosslinker, DCDA.

CH3H3C

H3C CH3

O O

OOHa Ha

Ha Ha

Hc

Hb Hd

Hc

Hd Hb

a

b

c

d e

e

CHCl3

382

O

O OO

O On

O

O O

O

baseO

O OO

O On

OO

OO

O

OO

O

O

O

O

O O

O

n

OO

O

O

OO

O

O

Figure 8.2. Synthesis of crosslinked networks via base catalyzed Michael addition.

383

8.4.2 Acid Catalyzed Degradation of Networks

The Michael addition networks containing DCDA were readily degraded using strong

acid catalysts such as trifluoroacetic acid (TFA) in dichloromethane, concentrated HCl or

p-toluenesulfonic acid (p-TSA) in dioxane (Figure 8.3) at 25 oC. The most effective acid was

TFA, which converted the network into completely soluble components in 50 s in

dichloromethane (20 vol%). The gel sample dissolved rapidly into soluble material and gel

was not visible after 50 s. In the case of p-TSA (10 wt% in dioxane), the networks degraded

into completely soluble components over a period of 30 min at 25 oC. In contrast, control

networks did not degrade under these conditions. The presence of poly(ethylene glycol)

linkages in the networks allowed limited swellability in water, permitting degradation in

concentrated HCl (35 wt%), which completely converted the sample into a dispersion of

insoluble particles within 3 min of stirring at room temperature. Photographs (Figure 8.4)

revealed the complete disintegration of the acid-cleavable DCDA containing networks using

p-TSA.

384

Figure 8.3. Degradation reactions of Michael addition networks containing DCDA using

p-toluenesulfonic acid.

OO

n

OO

O O

O

O

O

O

OO O O

OO

O

O

O

O

OO

OO

n

H+

OO

n

OO

O O

H

H

O

O

O

O

OO O O

OO

H

H

O

O

O

O

HHO

OO

O

n

385

Figure 8.4. Pictures of the degradation of DCDA containing Michael addition networks using

p-toluenesulfonic acid in dioxane. a) network sample as prepared, b) immersed in dioxane

with p-toluenesulfonic acid, c) after degradation.

a) b) c)

386

8.4.3 Thermal Degradation of Networks

The DCDA containing networks were also degraded thermally. Thermogravimetric

analysis revealed a stepwise degradation process (Figure 8.5). An initial weight loss occurred

at an onset temperature of 173 oC, which is consistent, but slightly higher than temperatures

typically observed in the thermal deprotection of t-BOC protected compounds (210 oC).714

The difference in degradation temperature may be attributed to the presence of residual base

catalyst. The samples released nearly 28 wt% in that degradation step, which corresponded

well to the weight loss from the volatile diene byproduct (theoretical weight loss = 26%).

714 Ying, J.; Fréchet, J.; Willson, C. Poly(vinyl-t-butyl carbonate) synthesis and thermolysis to poly(vinyl alcohol). Polym Bull 1987, 17, 1-6.

387

0

10

20

30

40

50

60

70

80

90

100

0 100 200 300 400 500 600

Temperature (oC)

Wei

ght (

%)

0

1

2

3

4

5

6

7

8

9

10

dW/d

T (%

/o C)

WeightdW/dT

28wt%

Figure 8.5. Thermogravimetric analysis (TGA) and derivative weight loss curve for DCDA

containing network. The onset of weight loss at 173 oC corresponds to the theoretical mass of

the diene byproduct of DCDA at complete conversion.

388

8.4.4 Mechanical Characterization of Networks

Dynamic mechanical analysis (DMA) of the acid-cleavable diacrylate containing

networks (Figure 8.6) revealed a glass transition for the network at 17 oC (tan delta

maximum), which was significantly higher than the Tg for PEG (-60 oC)715 due to the

restrictions on chain mobility imposed with the crosslink points. The Tg corresponded well

with values obtained for PEG diacrylate free radically crosslinked networks (Tg = 19 oC for

Mn = 600). 716 The rubbery plateau modulus for the network was 1.2 MPa, which

corresponded to an elastomeric material. This modulus is in a typical range for networks

composed of end-linked oligomers due to the relatively low crosslink density and mobility of

the linear oligomeric chains in the network. The breadth of the tan delta peak was relatively

narrow (full-width at half maximum, FWHM = 15 oC) and the peak was symmetric,

indicating a relatively narrow distribution of segmental relaxation times. Cook et al. reported

FWHM values as low as 21 oC for the tan delta curve of vinyl ester resins.717 Generally, the

breadth of the tan delta peak increases with crosslink density717 and network cooperativity.718

715 Tormala, P. Determination of glass transition temperature of poly(ethylene glycol) by spin probe technique. Eur Polym J 1974, 10, 519-21. 716 Priola, A.; Gozzelino, G.; Ferrero, F.; Malucelli, G. Properties of polymeric films obtained from u.v. cured poly(ethylene glycol) diacrylates. Polymer 1993, 34, 3653-7. 717 Scott, T.; Cook, W.; Forsythe, J. Kinetics and network structure of thermally cured vinyl ester resins. Eur Polym J 2002, 38, 705-16. 718 Tyberg, C.; Bergeron, K.; Sankarapandian, M.; Shih, P.; Loos, A.; Dillard, D.; McGrath, J.; Riffle, J.; Sorathia, U. Structure–property relationships of void-free phenolic–epoxy matrix materials. Polymer 2000, 41, 5053-62.

389

0

1

2

3

[ ???

?] T

an D

elta

0.1

1

10

100

1000

10000

Stor

age

Mod

ulus

(MPa

)

-80 -30 20 70Temperature (C)

_____ Storage Modulus

- - - - - - Tan Delta


Figure 8.6. Dynamic mechanical analysis (DMA) of acid cleavable diacrylate network.

390

Tensile analysis (Figure 8.7) of the acid-cleavable diacrylate networks revealed a tensile

strength of 0.39 ± 0.09 MPa and strain at break of 84 ± 12%. The Young’s modulus of the

network was 0.75 ± 0.10 MPa. The networks did not exhibit a yield point in the tensile

curves, likely due to the subambient glass transition temperature. These mechanical property

values were consistent with previous measurements on Michael addition networks.719 The

corresponding molecular weight between crosslink points (Mc) obtained from the Young’s

modulus value was 9900 g/mol. This is significantly higher than the poly(ethylene glycol)

bis(acetoacetate) molecular weight (Mn = 600 g/mol), and suggested less than difunctionality

for the acetoacetate functional groups as well as the possible presence of dangling ends in the

networks.

719 Mather, B. D.; Miller, K. M.; Long, T. E. Novel Michael Addition Networks Containing Poly(propylene glycol) Telechelic Oligomers. Macromol Chem Phys 2006, 207, 1324-33.

391

Figure 8.7. Tensile analysis of acid-cleavable Michael addition network.

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0 10 20 30 40 50 60 70 80 90 100

Tensi

le s

tress

(M

Pa)

Tensile strain (%)

392

8.5 Conclusion

This manuscript reports the first acid-cleavable network synthesized through Michael

addition chemistry. A novel acid-labile diacrylate, DCDA, was synthesized in a single step

from readily available starting materials. Networks containing DCDA were synthesized

through facile base-catalyzed Michael addition of telechelic poly(ethylene glycol)

bis(acetoacetate)s, which allowed curing at ambient temperature. The products had rubbery

plateau modulus values of 1.2 MPa and glass transitions of 17 oC. Cleavage of the networks

into soluble components was readily achieved in the presence of a variety of acids including

trifluoroacetic acid in seconds. Thermal degradation was also achieved and

thermogravimetric measurements revealed a sharp weight loss at 173 oC that corresponded

closely to the expected weight loss for the diene byproduct.

8.6 Acknowledgement

The authors would like to acknowledge the financial support of Rohm and Haas

Company and the Department of Energy (DE-FG36-04GO14317). This material is based

upon work supported by the U.S. Army Research Laboratory and the U.S. Army Research

Office under contract/grant number DAAD19-02-1-0275 Macromolecular Architecture for

Performance Multidisciplinary University Research Initiative (MAP MURI).

393

Chapter 9. Synthesis and Morphological Characterization of

Sulfonated Triblock Copolymers: Influence of High Sulfonate Levels

and Poly(ethylene-co-propylene) Molecular Weight

(Mather, B.D.; Beyer, F.L.; Handlin, D.L. Long, T.E. Polymer, to be submitted)

9.1 Abstract

Sulfonated poly(styrene-b-ethylene-co-propylene-b-styrene) block copolymers

containing short styrenic outer blocks (~1K) were synthesized via sequential anionic

polymerization with subsequent hydrogenation and sulfonation. The central rubbery block

molecular weight was systematically varied from 5K to 28K, which produced a range of

triblock copolymers with varied degrees of entanglement (Mc = 8100). Dynamic mechanical

analysis (DMA), small angle x-ray scattering (SAXS), atomic force microscopy (AFM),

tensile testing, and rheological measurements were used to fully characterize the triblock

polymers. The sulfonated block copolymers exhibited a rubbery plateau that lengthened upon

neutralization of the sulfonic acid groups to the corresponding sodium salt. SAXS and

tapping mode AFM both revealed microphase separated morphologies. Due to the low molar

content of sulfonated polystyrene outer blocks, morphologies with a continuous rubber phase

were expected, however, the absence of higher order peaks in the SAXS data prevented

determination of the specific morphology. SAXS analysis revealed increased interdomain

(Bragg) spacing with increasing poly(ethylene-co-propylene) molecular weight and decreased

interdomain spacing upon neutralization. Tensile testing revealed increased tensile strengths

394

upon neutralization and generally higher elongations for higher molecular weight rubbery

blocks due to higher levels of entanglement.

9.2 Introduction

Sulfonated block copolymer ionomers have re-emerged in recent years due to potential

applications in fuel cells,720 proton and ion-conducting membranes,721722723724

-725726727728

729 nanocomposites,

730,731 and elastomers.732 Ionomeric polymers include a number of commercial products

720 Kim, B.; Kim, J.; Jung, B. Morphology and transport properties of protons and methanol through partially sulfonated block copolymers. J Membr Sci 2005, 250, 175-82. 721 Liang, L.; Ying, S. Charge-mosaic membrane from gamma-irradiated poly(styrene-butadiene- 4-vinylpyridine) triblock copolymer. J Polym Sci B: Polym Phys 1993, 31, 1075 – 81. 722 Mokrini, A.; Del Rio, C.; Acosta, J. L. Synthesis and characterization of new ion conductors based on butadiene styrene copolymers. Solid State Ionics 2004, 166, 375-81. 723 Nacher, A.; Escribano, P.; Del Rio, C.; Rodriguez, A.; Acosta, J. L. Polymer Proton-Conduction Systems Based on Commercial Polymers. I. Synthesis and Characterization of Hydrogenated Styrene–Butadiene Block Copolymer and Isobutylene Isoprene Rubber Systems. J Polym Sci Part A: Polym Chem 2003, 41, 2809-15. 724 Kim, B.; Kim, J.; Jung, B. Proton conductivities and methanol permeabilities of membranes made from partially sulfonated polystyrene-block-poly(ethylene-ran-butylene)-block-polystyrene copolymers. J Membr Sci 2002, 207, 129-37. 725 Serpico, J. M.; Ehrenberg, S. G.; Fontanella, J. J.; Jiao, X.; Perahia, D.; McGrady, K. A.; Sanders, E. H.; Kellogg, G. E.; Wnek, G. E. Transport and Structural Studies of Sulfonated Styrene-Ethylene Copolymer Membranes. Macromolecules 2002, 35, 5916-21. 726 Elabd, Y. A.; Walker, C. W.; Beyer, F. L. Triblock copolymer ionomer membranes Part II. Structure characterization and its effects on transport properties and direct methanol fuel cell performance. J. Membr. Sci. 2004, 231, 181-8. 727 Won, J.; Park, H. H.; Kim, Y. J.; Choi, S. W.; Ha, H. Y.; Oh, I. H.; Kim, H. S.; Kang, Y. S.; Ihn, K. J. Fixation of Nanosized Proton Transport Channels in Membranes. Macromolecules 2003, 36, 3228-34. 728 Kim, J.; Kim, B.; Jung, B.; Kang, Y. S.; Ha, H. Y.; Oh, I. H.; Ihn, K. J. Effect of Casting Solvent on Morphology and Physical Properties of Partially Sulfonated Polystyrene-blockpoly(ethylene-ran-butylene)-block-polystyrene Copolymers. Macromol Rapid Commun 2002, 23, 753-6. 729 Won, J.; Choi, S. W.; Kang, Y. S.; Ha, H. Y.; Oh, I. H.; Kim, H. S.; Kim, K. T.; Jo, W. H. Structural characterization and surface modification of sulfonated polystyrene–(ethylene–butylene)–styrene triblock proton exchange membranes. J Membr Sci 2003, 214, 245-57. 730 Mauritz, K. A.; Storey, R. F.; Reuschle, D. A.; Tan, N. B. Poly(styrene-b-isobutylene-b-styrene) block copolymer ionomers (BCPI) and BCPI/silicate nanocomposites. 2. Na+BCPI sol–gel polymerization

395

such as Nafion™, which is an ion-conductive sulfonated fluoropolymer, and the tough,

abrasion-resistant ethylene sodium methacrylate copolymer, Suryln™. Sulfonated block

copolymers exhibit morphological differences from their non-ionic analogs due to the

presence of ionic aggregates, which serve as additional physical crosslinks with microphase

separation.733,734 According to the Eisenberg-Hird-Moore (EHM) model, ionomers contain

multiplets, which consist of several ion pairs that overlap to form clusters and surrounding

polymer chains of reduced mobility that give rise to a second, higher Tg.735 The ionic

clusters dominate the properties of the polymer at low ion concentrations due to the

corresponding large volume fraction of chains with reduced mobility (~50 vol% clusters at 4

mol% ion content).736 The strength of the association of ionic groups also increases the

Flory-Huggins interaction parameter, χ, for microphase separation and enables lower block

molecular weights for microphase separation since χN, where N is the degree of

polymerization.737

Sulfonated block copolymers have generated interest as elastomers due the lengthening

templates. Polymer 2002, 43, 5949-58. 731 Mauritz, K. A.; Blackwell, R. I.; Beyer, F. L. Viscoelastic properties and morphology of sulfonated poly(styrene-b-ethylene/butylene-b-styrene) block copolymers (sBCP), and sBCP/[silicate] nanostructured materials. Polymer 2004, 45, 3001-16. 732 Chun, Y. S.; Weiss, R. A. The development of the ionic microphase in sulfonated poly(ethylene-co-propylene-co-ethylidene norbornene) ionomers during physical aging above Tg. Polymer 2002, 43, 1915-23. 733 Eisenberg, A. Clustering of Ions in Organic Polymers. A Theoretical Approach. Polymer 1970, 3, 147-154. 734 Mohajer, Y.; Tyagi, D.; Wilkes, G. L.; Storey, R. F.; Kennedy, J. P. New Polyisobutylene Based Model Ionomers. 3. Further Mechanical and Structural Studies. Polymer Bulletin 1982, 8, 47-54. 735 Eisenberg, A.; Hird, B.; Moore, R. B. A New Multiplet-Cluster Model for the Morphology of Random Ionomers. Macromolecules 1990, 23, 4098-107. 736 Eisenberg, A.; Kim, J. S., Introduction to Ionomers. John Wiley and Sons: New York, 1998. 737 Leibler, L. Theory of Microphase Separation in Block Copolymers. Macromolecules 1980, 13, 1602-17.

396

of the rubbery plateau to higher temperatures compared to non-sulfonated analogs.738,739

The higher temperature “service window” is a consequence of strong ionic interactions

between sulfonated styrene residues, which reinforce the hard domains. Several workers have

observed significantly improved high temperature (100 oC) tensile strengths for sulfonated

block copolymers compared to non-sulfonated analogs.740741

- 742 In fact, the persistence of

ionic interactions to 300 oC was established using variable temperature SAXS.743 Despite

enhanced mechanical properties at high temperature, ionomers are often melt processible,744745

-

746 particularly in the presence of ionic plasticizers such as zinc stearate.747,748 Above the

738 Bagrodia, S.; Wilkes, G. L.; Kennedy, J. P. New Polyisobutylene-Based Model Elastomeric Ionomers. VIII. Thermal-Mechanical Analysis. J Appl Polym Sci 1985, 30, 2179-93. 739 Mani, S.; Weiss, R. A.; Williams, C. E.; Hahn, S. F. Microstructure of Ionomers Based on Sulfonated Block Copolymers of Polystyrene and Poly(ethylene-alt-propylene). Macromolecules 1999, 32, 3663-70. 740 Balas, J. G.; Gergen, W. P.; Willis, C. L.; Pottick, L. A.; Gelles, R.; Weiss, R. A. Sulfonated block copolymers. US Patent 5239010, 1993. 741 Pottick, L. A.; Willis, C. L.; Gelles, R. Selectively sulfonated block copolymers/extender oils. US Patent 5516831, 1996. 742 Weiss, R. A.; Sen, A.; Pottick, L. A.; Willis, C. L. Block copolymer ionomers: 2. Viscoelastic and mechanical properties of sulphonated poly(styrene-ethylene/butylene-styrene) Polymer 1991, 32, 2785-92. 743 Lu, X.; Steckle, W. P.; Hsiao, B.; Weiss, R. A. Thermally Induced Microstructure Transitions in a Block Copolymer Ionomer. Macromolecules 1995, 28, 2831-9. 744 Mohajer, Y.; Tyagi, D.; Wilkes, G. L.; Storey, R. F.; Kennedy, J. P. New Polyisobutylene Based Model Ionomers. 3. Further Mechanical and Structural Studies. Polymer Bulletin 1982, 8, 47-54. 745 Bagrodia, S.; Pisipati, R.; Wilkes, G. L.; Storey, R. F.; Kennedy, J. P. Melt Rheology of Ion-Containing Polymers. I. Effect of Molecular Weight and Excess Neutralizing Agent in Model Elastomeric Sulfonated Polyisobutylene-Based Ionomers. J Appl Polym Sci 1984, 29, 3065-73. 746 Earnest, T. R.; MacKnight, W. J. Effect of Hydrogen Bonding and Ionic Aggregation on the Melt Rheology of an Ethylene-Methacrylic Acid Copolymer and its Sodium Salt. J Polym Sci: Polym Phys Edn 1978, 16, 143-57. 747 Antony, P.; Bhattacharya, A. K.; De, S. K. Ionomeric polyblends of zinc salts of maleated EPDM rubber and poly(ethylene-co-acrylic acid). II. Effect of zinc stearate on processability J Appl Polym Sci 1999, 71, 1257-65. 748 Duvdevani, I.; Lundberg, R. D.; Wood-Cordova, C.; Wilkes, G. L., Modification of Ionic Associations by Crystalline Polar Additives. In ACS Symposium Series: Coulombic Interactions in Macromolecular Systems, Eisenberg, A.; Bailey, F. E., Eds. American Chemical Society: Washington DC, 1986; Vol. 302, pp 185-99.

397

ionic Tg, ion hopping phenomena, which possess activation energies near 200 kJ/mol, are

proposed to permit polymeric mobility and softening.749 Decreases in compression set740

while maintaining ambient tensile properties742 were also observed earlier for sulfonated

block copolymers. Furthermore, the sulfonation process leads to improved chemical

resistance due to the lack of solubility of ionic domains in nonpolar solvents.

Sulfonated poly(styrene-b-ethylene/propylene-b-styrene) (SEPS) triblock copolymers

with short styrenic end blocks (~1000 g/mol) and variable length poly(ethylene/propylene)

(hydrogenated polyisoprene) rubber sequences containing 1,4-, 1,2- and 3,4-enchainment are

presented herein. The short styrene outer blocks enabled the placement of a controlled

number of metal sulfonate groups on the outer blocks, which contrasts from telechelic

ionomers, which possess only a single ionic group at the terminus. An objective of this work

is to elucidate the importance of the length of the rubbery block on morphology and

mechanical properties relative to the critical molecular weight for entanglement. This work

uniquely addresses a range of molecular weights, which were chosen to investigate the effects

of entanglement in the rubbery block as well as the high sulfonation levels in the relatively

short (1K) external blocks. Sulfonated block copolymers with relatively large styrenic

blocks (~10-20K) and low levels of sulfonation (<20%) were studied earlier, 750751

-752

753 and in

749 Hird, B.; Eisenberg, A. Sizes and stabilities of multiplets and clusters in carboxylated and sulfonated styrene ionomers. Macromolecules 1992, 25, 6466-74. 750 Chun, Y. S.; Weiss, R. A. The development of the ionic microphase in sulfonated poly(ethylene-co-propylene-co-ethylidene norbornene) ionomers during physical aging above Tg. Polymer 2002, 43, 1915-23. 751 Mani, S.; Weiss, R. A.; Williams, C. E.; Hahn, S. F. Microstructure of Ionomers Based on Sulfonated Block Copolymers of Polystyrene and Poly(ethylene-alt-propylene). Macromolecules 1999, 32, 3663-70. 752 Lu, X.; Steckle, W. P.; Weiss, R. A. Ionic Aggregation in a Block Copolymer Ionomer. Macromolecules 1993, 26, 5876-84. 753 Storey, R. F.; Baugh, D. W. Poly(styrene-b-isobutylene-b-styrene) block copolymers produced by

398

contrast, this manuscript deals with short styrenic blocks (1K) and higher levels of

sulfonation (~50%).

Storey et al. studied similar short outer block sulfonated

poly(styrene-b-ethylene-co-butylene-b-styrene) block copolymers, although these possessed

shorter (~500 g/mol) outer blocks and a three-arm star-shaped structure.754 Wilkes and

Storey also investigated linear telechelic ionomers, which contained a single ionic

functionality at each polyisobutylene chain end.755756 757

-758

759 In many instances, three-arm

telechelic ionomers are desirable due to the fact that trifunctionality leads to non-covalent

network formation whereas difunctionality for dimeric associations leads to chain

extension.756 In contrast, the multiple sulfonated styrene residues per chain end in our

current work enable network formation with a linear architecture.

Small-angle X-ray scattering (SAXS) is critical for morphological investigations of

traditional ionomers, microphase separated block copolymers, and block copolymer

living cationic polymerization. Part III. Dynamic mechanical and tensile properties of block copolymers and ionomers therefrom. Polymer 2001, 42, 2321-30. 754 Storey, R. F.; George, S. E.; Nelson, M. E. Star-Branched Block Copolymer Ionomers. Synthesis, Characterization, and Properties. Macromolecules 1991, 24, 2920-30. 755 Mohajer, Y.; Tyagi, D.; Wilkes, G. L.; Storey, R. F.; Kennedy, J. P. New Polyisobutylene Based Model Ionomers. 3. Further Mechanical and Structural Studies. Polymer Bulletin 1982, 8, 47-54. 756 Bagrodia, S.; Wilkes, G. L.; Kennedy, J. P. New Polyisobutylene-Based Model Elastomeric Ionomers. VIII. Thermal-Mechanical Analysis. J Appl Polym Sci 1985, 30, 2179-93. 757 Bagrodia, S.; Pisipati, R.; Wilkes, G. L.; Storey, R. F.; Kennedy, J. P. Melt Rheology of Ion-Containing Polymers. I. Effect of Molecular Weight and Excess Neutralizing Agent in Model Elastomeric Sulfonated Polyisobutylene-Based Ionomers. J Appl Polym Sci 1984, 29, 3065-73. 758 Bagrodia, S.; Mohajer, Y.; Wilkes, G. L.; Storey, R. F.; Kennedy, J. P. New Polyisobutylene-Based Ionomers. 5. The Effect of Molecular Weight on the Mechanical Properties of Tri-Arm Star Polyisobutylene-Based Model Ionomers. Polymer Bulletin 1983, 9, 174-80. 759 Mohajer, Y.; Bagrodia, S.; Wilkes, G. L.; Storey, R. F.; Kennedy, J. P. New Polyisobutylene Based Model Elastomeric Ionomers. VI. The Effect of Excess Neutralizing Agents on Solid-State Mechanical Properties. J Appl Polym Sci 1984, 29, 1943-50.

399

ionomers. 760761

-762

763 SAXS reveals the morphologies of block copolymers due to Bragg

diffraction maxima that identify characteristic microphase separated morphologies in

well-ordered samples. SAXS of ion-containing polymers typically displays an “ionomer

peak” at a characteristic length scale of 2-6 nm, which is generally assigned to microphase

separated ionic clusters. 761,764 -

,765

766 SAXS is particularly suited to the study of ionomers due to

the greater electron density contrast afforded from ion-containing materials.

9.3 Experimental

9.3.1 Materials

Styrene (99%) and isoprene (99%) monomers were purchased from Aldrich and

purified by vacuum distillation from calcium hydride and subsequent distillation from

dibutylmagnesium. The monomers were stored under nitrogen at -15 oC until use.

Sec-butyllithium (12% in hexanes/heptane) was purchased from FMC Lithium Co.

760 Serpico, J. M.; Ehrenberg, S. G.; Fontanella, J. J.; Jiao, X.; Perahia, D.; McGrady, K. A.; Sanders, E. H.; Kellogg, G. E.; Wnek, G. E. Transport and Structural Studies of Sulfonated Styrene-Ethylene Copolymer Membranes. Macromolecules 2002, 35, 5916-5921. 761 Mani, S.; Weiss, R. A.; Williams, C. E.; Hahn, S. F. Microstructure of Ionomers Based on Sulfonated Block Copolymers of Polystyrene and Poly(ethylene-alt-propylene). Macromolecules 1999, 32, 3663-70. 762 Tsujita, Y.; Hayashi, N.; Yamamoto, Y.; Yoshimizu, H.; Kinoshita, T.; Matsumoto, S. SAXS study on ionic aggregates of styrene-isoprene-sulfonated isoprene terpolymer ionomer J Polym Sci Part B: Polym Phys 2000, 38, 1307-11. 763 Storey, R. F.; Baugh, D. W. Poly(styrene-b-isobutylene-b-styrene) block copolymers and ionomers therefrom: morphology as determined by small-angle X-ray scattering and transmission electron microscopy. Polymer 2000, 41, 3205-11. 764 Lu, X.; Steckle, W. P.; Weiss, R. A. Ionic Aggregation in a Block Copolymer Ionomer. Macromolecules 1993, 26, 5876-84. 765 Benetatos, N. M.; Heiney, P. A.; Winey, K. I. Reconciling STEM and X-ray Scattering Data from a Poly(styrene-ran-methacrylic acid) Ionomer: Ionic Aggregate Size. Macromolecules 2006, 39, 5174-6. 766 Register, R.A.; Cooper, S.L. Anomalous small-angle x-ray scattering from nickel-neutralized ionomers. 1. Amorphous polymer matrixes. Macromolecules, 1990, 23, 310-17.

400

Dibutylmagnesium (1.0 M in heptane) and triethylaluminum (1.0 M in hexanes), anhydrous

1,2-dichloroethane (99.8%) and citric acid (99.5%) were purchased from Aldrich and used as

received. Nickel (II) 2-ethylhexanoate (8% in mineral spirits) was purchased from Shepherd

Chemicals and used as received. Cyclohexane was purified using molecular sieves and

alumina-containing columns under nitrogen.

9.3.2 Synthesis of Poly(styrene-b-isoprene-b-styrene) Triblock Copolymers

Polymerizations were conducted in a 600-mL glass reactor fitted with magnetic stirring,

steam/cold water heating/cooling coils, a thermocouple and temperature controller as well as

ports for introducing nitrogen, cyclohexane, monomers and initiators and for draining and

venting.767 The reactor was filled with 400 mL dry cyclohexane under nitrogen and

maintained at 40 oC. Styrene, 2.06 mL, (18.1 mmol) was injected into the reactor, and 1.60

mL sec-butyllithium (2.0 mmol, 1.25 M in hexanes) was subsequently added to rapidly form

an orange color. The polymerization was allowed to proceed for 5 h and samples were

periodically removed to ensure complete monomer conversion. Isoprene (55 mL, 550 mmol)

was injected and the color immediately changed to light yellow. The polymerization was

continued for 18.5 h and multiple samples were removed to ensure complete conversion of

isoprene monomer. The final styrene aliquot (2.10 mL, 18.1 mmol) was injected and again

polymerized for 5 h at 40 oC. Long polymerization times were used to ensure complete

monomer consumption. The polymerization was then terminated with degassed methanol,

767 Hoover, J. M.; Ward, T. C.; McGrath, J. E. The influence of hydrogenation on star block copolymers based on tertiary-butylstyrene-isoprene-divinylbenzene. Polym Prepr, Am Chem Soc, Div Polym Chem 1985, 26, 253-4.

401

precipitated into methanol, dried in vacuo at 50 oC, and stored in a freezer at -15 oC in the

absence of inhibitor. SEC analysis of the samples and final product revealed block

molecular weights of 1.2K-17.1K-0.5K (1.0K-19.9K-1.0K by 1H NMR) and a molecular

weight distribution (Mw/Mn) of 1.01.

9.3.3 Hydrogenation of Poly(styrene-b-isoprene-b-styrene) Triblock Copolymers

Hydrogenations were conducted in a similar reactor that was used for polymerizations.

Nickel octoate/triethylaluminum hydrogenation catalyst was first prepared by adding a

triethylaluminum solution in hexanes (4.8 mL, 1.0 M, 4.8 mmol) to a nickel 2-ethylhexanoate

solution (5.7 mL, 1.34 mmol) in 20 mL dry cyclohexane dropwise with stirring under

nitrogen. The catalyst solution was allowed to stir under nitrogen for 15 min prior to use.

Poly(styrene-b-isoprene-b-styrene) (6.0 g) was dissolved in 100 mL dry cyclohexane under

nitrogen and cannulated into the glass reactor fitted with magnetic stirrer and filled with 400

mL of cyclohexane. Finally, a few drops of catalyst solution were cannulated into the reactor

and the reactor was pressurized to 90 psig with hydrogen gas and heated to 50 oC.

Hydrogenation levels were monitored with periodic sampling, removing the catalyst with

aqueous citric acid washes, and obtaining 1H NMR spectra. The hydrogenations were

performed to greater than 99% conversion of the olefinic sites. The catalyst was removed by

washing with citric acid solution (10 wt%) for 24 - 48 h as described in the earlier

literature.768

768 Hoover, J. M.; Ward, T. C.; McGrath, J. E. The influence of hydrogenation on star block copolymers based on tertiary-butylstyrene-isoprene-divinylbenzene. Polym Prepr, Am Chem Soc, Div Polym Chem 1985, 26, 253-4.

402

9.3.4 Sulfonation of Poly(styrene-b-ethylene-co-propylene-b-styrene) Triblock

Copolymers

Poly(styrene-b-ethylene-co-propylene-b-styrene) triblock copolymer (4.20 g) was

charged to a 500-mL round-bottomed flask and dissolved in 140 mL cyclohexane at 50 oC.

Acetyl sulfate (25 equivalents relative to styrene) was generated separately through the

addition of sulfuric acid (10.1 g, 101 mmol) to acetic anhydride (16.6 g, 163 mmol) in

1,2-dichloroethane (100 mL) at 0 oC. After stirring vigorously, the acetyl sulfate was added to

the polymer solution dropwise through an addition funnel. The sulfonation reaction

proceeded for 24 h. The polymer was isolated through dripping the crude product into boiling

water, which also served to remove the solvent. Water was repeatedly exchanged to

completely remove the acetic and sulfuric acid impurities. The polymer was then dissolved in

tetrahydrofuran and dialyzed against deionized water to further remove acidic impurities.

Final isolation involved rotary evaporation of the aqueous suspension followed by drying at

reduced pressure at 25 oC for 24 h.

9.3.5 Titration and Neutralization of Sulfonated

Poly(styrene-b-ethylene-co-propylene-b-styrene)

Sulfonated SEPS block copolymer (0.116 g) was dissolved in tetrahydrofuran (30 mL)

and titrated with standardized 0.023 M NaOH (aq) (0.75 mL) using thymol blue as an

indicator. The degree of sulfonation (62%, relative to styrene content) was determined from

the average of three titrations. A larger portion of polymer (3.89 g) was subsequently

neutralized via addition of 45.1 mL (1 equiv) of 0.023 M NaOH. The neutralized polymer

403

was then isolated using rotary evaporation of the solvent mixture and drying under reduced

pressure at 40 oC for 48 h.

9.3.6 Small Angle X-Ray Scattering (SAXS) Measurements

Block copolymers that contained pendant sulfonic acids were dissolved in THF and cast

in Teflon™ molds whereas sodium sulfonated derivatives were cast from toluene/methanol

(95/5 w/w). The films were dried in a vacuum oven at room temperature for 4 days and stored

at -15 oC until use. SAXS data were collected on the Army Research Laboratory (ARL)

SAXS instrument, located at Aberdeen Proving Ground, MD. CuKα X-ray radiation was

generated using a Rigaku Ultrax18 rotating anode X-ray generator operated at 40 kV and 115

mA. A Ni foil was used to filter out all radiation except the CuKα doublet, with an average

wavelength, λ, of 1.542 Ǻ. The ARL instrument uses a Molecular Metrology camera with 300,

200 and 600 μm pinholes for X-ray collimation. Two-dimensional data sets were collected

using a Molecular Metrology 2D multi-wire area detector located approximately 1.5 m from

the sample. After azimuthal averaging, the raw data were corrected for detector noise,

absorption, and background noise. The data were then placed on an absolute scale using a

glassy carbon sample 1.07 mm thick, previously calibrated at the Advanced Photon Source of

the Argonne National Laboratory as a secondary standard. The one-dimensional intensity

data are given as a function of the magnitude of the reciprocal scattering vector, q, where q =

4π·sin(θ)/λ, and 2θ is the scattering angle. All data reduction and analysis were performed

using Wavemetrics Igor Pro v. 5.04.

404

9.3.7 Atomic Force Microscopy (AFM) Measurements

A Veeco MultiMode™ scanning probe microscope and a Nanoscope IVa controller

were used for tapping-mode AFM. All sulfonated block copolymers were spun onto silicon

wafers and dried under vacuum; imaging was performed at a set-point ratio of 0.6 at

magnifications of 1 μm x 1 μm. Veeco’s Nanosensor silicon tips having spring constants of

10-130 N/m were utilized for imaging.

9.3.8 Size Exclusion Chromatography

Size-exclusion chromatography (SEC) was performed at 40 °C in HPLC grade

tetrahydrofuran at a flow rate of 1 mL/min using a Waters size exclusion chromatography

instrument equipped with an autosampler, 3 in-line 5 μm PLgel MIXED-C columns.

Detectors included a Waters 410 differential refractive index (DRI) detector operating at 880

nm, and a Wyatt Technologies miniDAWN multiangle laser light scattering (MALLS)

detector operating at 45o, 90o and 135o and 690 nm, which was calibrated with polystyrene

standards. The refractive index increment (dn/dc) was calculated online. All molecular weight

values reported are absolute molecular weights obtained using the MALLS detector.

9.3.9 Dynamic Mechanical Analysis, Thermal and Rheological Studies

Dynamic mechanical measurements were performed on a TA Instruments Q-800 DMA

under nitrogen at a heating rate of 3 oC/min at 1 Hz. The solvent cast samples were

measured in film tension mode and cut into 5 mm wide strips using a razor blade.

Rheological measurements were conducted using a TA Instruments AR 1000 rheometer in

405

parallel plate geometry using 25 mm plates and a 1 mm gap. Solvent cast films were cut to

size and placed within the rheometer plates. Measurements of the storage modulus and loss

modulus were performed between -30 oC and 60 oC and at a constant strain of 3%.

Time-temperature superposition (TTS) allowed the development of master curves for the

modulus measurements. Differential scanning calorimetry (DSC) was performed on a

Perkin Elmer Pyris 1 instrument under a nitrogen flush at a heating rate of 10 ºC/min. 1H

NMR spectroscopic data was collected in CDCl3 on a Varian 400 MHz spectrometer at

ambient temperature.


9.4.1 Sulfonated SEPS Triblock Polymer Synthesis

Poly(styrene-b-isoprene-b-styrene) (SIS) triblock copolymers were synthesized via

anionic polymerization using sequential monomer addition (Figure 9.1). Anionic

polymerization techniques allowed control of molecular weight and afforded narrow

molecular weight distribution, well-defined block copolymers for subsequent fundamental

studies (Table 9.1). SEC analysis during the polymerization demonstrated complete

crossover as well as complete conversion of each block in the time intervals chosen, which

established the absence of tapering between the blocks (Figure 9.2). Short styrene outer

block (~1K) were targeted, while variable length rubber sequences (4K-28K) allowed a study

of the effect of rubber block molecular weight.

Selective hydrogenation of the isoprene blocks was achieved using a conventional

nickel/aluminum catalyst which is critical due to the reactivity of olefins towards subsequent

406

sulfonating reagents. The extent of hydrogenation was monitored with 1H NMR spectroscopy

which indicated conversion near 99% and above. Sulfonation was accomplished in a mixture

of cyclohexane and dichloroethane using acetyl sulfate, which has been recognized as a mild

sulfonating agent.769 Although excess sulfonating agent was used relative to styrene

repeating units, the sulfonation of hydrogenated diene-containing block copolymers typically

reached a maximum conversion near 50-60 mol%, as determined through titration

measurements, which was presumed due to micelle formation during the reaction in

cyclohexane/dichloroethane. In fact, solution turbidity was observed as sulfonation occurred.

Low efficiencies were observed earlier in sulfonation of block copolymers with acetyl

sulfate,770,771 and plateau levels of sulfonation from 60%772 to 80%773 were noted in some

cases. The sulfonated block copolymers were neutralized with stoichiometric quantities of

sodium hydroxide, which was added to the sulfonic acid functionalized polymer solutions in

THF.

769 La Combe, E.M.; Miller, W.P Furansulfonic acids and their polymers. US Patent 3182042, 1965. 770 Kim, B.; Kim, J.; Jung, B. Proton conductivities and methanol permeabilities of membranes made from partially sulfonated polystyrene-block-poly(ethylene-ran-butylene)-block-polystyrene copolymers. J Membr Sci 2002, 207, 129-37. 771 Elabd, Y. A.; Walker, C. W.; Beyer, F. L. Triblock copolymer ionomer membranes Part II. Structure characterization and its effects on transport properties and direct methanol fuel cell performance. J. Membr. Sci. 2004, 231, 181-8. 772 Balas, J.G.; Gergen, W.P.; Willis, C.L.; Pottick, L.A.; Gelles, R.; Weiss, R.A. Sulfonated block copolymers. US Patent 5239010, 1993. 773 Elabd, Y.A.; Napadensky, E. Sulfonation and characterization of poly(styrene-isobutylene-styrene) triblock copolymers at high ion-exchange capacities. Polymer 2004, 45, 3037-43.

407

s-BuLicyclohexane40oC

Li

3) methanol

Hx

x y xz

1) isoprene2) styrene

H

50 ºC, 90 psicyclohexane

HBu BuNi(oct)2/AlEt3

x y z x x y z x

50 ºC, 12 hC2H6Cl2cyclohexane

HBuH2SO4 / Ac2O

HBu

SO3H SO3H

x y z x x y z x

Figure 9.1. Synthesis of sulfonated block copolymers via sequential addition anionic

polymerization.

408

Figure 9.2. SEC analysis of aliquots removed from the polymerization reaction after each

block (9K sample)

Minutes16.00 17.00 18.00 19.00 20.00 21.00 22.00 23.00 24.00 25.00 26.00 27.00 28.00

Step 1 Step 2 Final

Mn = 11100 Mw/Mn = 1.01

Mn = 10700 Mw/Mn = 1.01

Mn = 900 Mw/Mn = 1.15

409

Table 9.1. Compositional analysis of block copolymers.

ID

Calculated SECa

Block Molecular

Weights

(g/mol)

Calculated NMRb

Block Molecular

Weights

(g/mol)

Mw/Mn

Percent

Styrene

Contentb

(wt%)

Percent

Hydrogenation

(mol %) b

Percent

Sulfonationc

(mol %

styrene)

SEPS

Tg d

(ºC)

4K 1.2K-4.8K-1.7K 0.9K-3.8K-1.0K 1.07 33.3 98.5 21 -53,-12

9K 1.0K-10.0K-0.4K 0.9K-8.8K-1.1K 1.01 18.5 99.4 45 -54

20K 1.2K-17.1K-0.5K 1.0K-19.9K-1.0K 1.01 9.1 99.8 62 -57

28K 1.0K-27.5K-0.8K 0.8K-28.2K-1.4K 1.02 7.2 98.7 46 -56

a SEC analysis, calculated from block molecular weights adjusted for hydrogenation

b 1H NMR analysis

c Titration against 0.02 M NaOH(aq) in tetrahydrofuran

d DSC, 10oC/min, N2

410

9.4.2 Dynamic Mechanical Analysis (DMA) of Sulfonated SEPS Triblock Polymers

Upon sulfonation, the block copolymers changed from viscous liquids to elastic solids.

DMA of the sulfonated block copolymers revealed the microphase separated morphology

(Figure 9.3). DSC measurements on the unsulfonated SEPS precursors revealed a single Tg

in most cases near -55 oC, however a second Tg near -12 oC was observed for the 5K sample,

which had the highest styrene segment content. The Fox-Flory equation, which is based on

free volume considerations, predicts a Tg of 15 oC for 1000 g/mol endblocks based on a

treatment by Storey and Baugh.774

The DMA revealed glass transitions in the sulfonated block copolymers that occurred at

-45 to -30 oC (tan δ peak), somewhat higher than the DSC measurement. Above this

rubbery phase glass transition, a plateau in modulus existed for the sulfonic acid containing

polymers that reached 60 oC, while the rubbery plateau for sodium sulfonate form reached

nearly 150 oC. The high temperature mechanical performance of the ionomers was in

agreement with the stronger association of ionic groups (SO3Na) in comparison to the

hydrogen bonding of sulfonic acid groups. Wilkes et al. observed a similar extension of the

rubbery plateau upon neutralization for telechelic polyisobutylene ionomers from 25 oC to

100 oC775 and Weiss et al. observed a similar trend for sulfonated SEPS possessing longer

styrene blocks.776 The softening temperature of the ionomers in the present study was lower

774 Storey, R. F.; Baugh, D. W. Poly(styrene-b-isobutylene-b-styrene) block copolymers produced by living cationic polymerization. Part III. Dynamic mechanical and tensile properties of block copolymers and ionomers therefrom. Polymer 2001, 42, 2321-30. 775 Bagrodia, S.; Wilkes, G. L.; Kennedy, J. P. New Polyisobutylene-Based Model Elastomeric Ionomers. VIII. Thermal-Mechanical Analysis. J Appl Polym Sci 1985, 30, 2179-93. 776 Mani, S.; Weiss, R. A.; Williams, C. E.; Hahn, S. F. Microstructure of Ionomers Based on Sulfonated Block Copolymers of Polystyrene and Poly(ethylene-alt-propylene). Macromolecules 1999, 32, 3663-70.

411

than the ionic Tg observed for sulfonated polystyrene, which occurred near 210 oC according

to DMA at 1 Hz.777 However, it was noted earlier that the ionic Tg for sulfonated

styrene-ethylene-butylene random copolymers (180 oC) was also significantly below

sulfonated polystyrene.778

The magnitude of the rubbery plateau modulus appeared to be highest for the 5K rubber

block sample and lower for 10K and above samples, but the differences in modulus were less

distinguishable at higher molecular weights. This was attributed to the fact that the higher

molecular weight samples were significantly above the critical molecular weight for

entanglement for poly(ethylene-co-propylene) (Mc = 8100 g/mol). 779 Loveday et al.

observed near-superimposable storage modulus DMA curves for telechelic sulfonated

polyisobutylene ionomers with molecular weights ranging from 20K to 50K (both above the

entanglement molecular weight).780 For each rubber block molecular weight in the present

study, the sodium sulfonated polymer had slightly higher moduli than the sulfonic acid-

functionalized polymer in the dynamic mechanical spectrum. Wilkes et al. observed higher

rubber plateau modulus values for neutralized telechelic sulfonated polyisobutylene ionomers

compared to sulfonic acid analogues, indicating greater strength of the ionic association.781

777 Hird, B.; Eisenberg, A. Sizes and stabilities of multiplets and clusters in carboxylated and sulfonated styrene ionomers. Macromolecules 1992, 25, 6466-74. 778 Nishida, M.; Eisenberg, A. Dynamic Mechanical Study of Sodium Sulfonated Random Ionomers Based on Hydrogenated Styrene-Butadiene Copolymer. Macromolecules 1996, 29, 1507-15. 779 Fetters, L. J.; Lohse, D. J.; Milner, S. T.; Graessley, W. W. Packing Length Influence in Linear Polymer Melts on the Entanglement, Critical, and Reptation Molecular Weights. Macromolecules 1999, 32, 6847-51. 780 Loveday, D.; Wilkes, G. L.; Lee, Y.; Storey, R. F. Investigation of the Structure and Properties of Polyisobutylene-Based Telechelic Ionomers of Narrow Molecular Weight Distribution. II. Mechanical. J Appl Polym Sci 1997, 63, 507-19. 781 Bagrodia, S.; Wilkes, G. L.; Kennedy, J. P. New Polyisobutylene-Based Model Elastomeric Ionomers. VIII. Thermal-Mechanical Analysis. J Appl Polym Sci 1985, 30, 2179-93.

412

Figure 9.3. Dynamic mechanical analysis of sulfonated SEPS polymers a) sodium sulfonate

form b) sulfonic acid form. The higher temperature service window for the neutralized

polymers is due to the strong ionic interactions present.

4K

9K

20K

28K

a)

4K 9K 20K

28K

b)

413

The sodium sulfonated block copolymers all exhibited an intermediate transition in the

dynamic mechanical spectrum, which appeared as a small decrease in storage modulus and a

peak in the tan δ curves near 25-60 oC and was not observed in the sulfonic acid forms. The

transition broadened, diminished in magnitude, and increased in temperature with increased

rubber block molecular weight. Similar, intermediate mechanical transitions in ionenes near 0

oC were attributed to molecular motions in the ion-rich phase.782

The dynamic mechanical behavior of the sulfonated block ionomers sharply contrasted

with the classical behavior of random ionomers. For random ionomers, both the rubbery

plateau moduli and glass transition temperatures increase dramatically with sulfonation level

due to the higher physical crosslink density.783,784 In the current study, however, the

multiplets and clusters were restricted to microphase separated domains and the continuous

rubber domains were subject only to effects of entanglement and physical crosslink density

due to the microphase separated domains. Thus, the block copolymers studied herein

exhibited increased rubber phase glass transition temperatures with decreasing rubber block

molecular weight. In a similar fashion, for covalent networks, the glass transition

temperature increased linearly with inverse rubber block molecular weight,785 which is

consisten with the trends observed for the sodium sulfonated block copolymers (Figure 9.4).

782 Tsutsui, T.; Tanaka, R.; Tanaka, T. Mechanical relaxations in some ionene polymers. I. Effect of ion concentration. J Polym Sci Polym Phys Ed 1976, 14, 2259-71. 783 Nishida, M.; Eisenberg, A. Dynamic Mechanical Study of Sodium Sulfonated Random Ionomers Based on Hydrogenated Styrene-Butadiene Copolymer. Macromolecules 1996, 29, 1507-15. 784 Eisenberg, A.; Kim, J. S., Introduction to Ionomers. John Wiley and Sons: New York, 1998. 785 Andrady, A. L.; Sefcik, M.D. Glass transition in poly(propylene glycol) networks. J Polym Sci: Polym Phys Ed 1983, 21, 2453-63.

414

R2 = 0.9761

-45

-40

-35

-30

-25

-20

0 0.00005 0.0001 0.00015 0.0002 0.00025 0.0003

1/Mn Rubber Block

Tg (o C

)

Figure 9.4. Glass transition temperatures of sodium sulfonated SEPS copolymers as a

function of rubber block molecular weight.

415

9.4.3 Tensile Characterization of Sulfonated SEPS Polymers

Tensile characterization is an essential technique for the characterization of elastomers.

The tensile properties of the sulfonated SEPS block copolymers are listed in Table 9.2. The

sulfonic acid (SO3H) functional polymers consistently exhibited lower tensile strengths than

the corresponding salt (SO3Na) forms (Figure 9.5). Generally, higher molecular weight

rubber block samples exhibited higher elongations and similar tensile strengths. This is

expected since higher strain must be applied to overcome greater levels of entanglements.

Wilkes et al.786 and Loveday et al.787 also observed increasing elongation with molecular

weight for three-arm sulfonated polyisobutylene telechelic ionomers and Storey et al.

observed the same trend for sulfonated three-arm

poly(styrene-b-ethylene-co-butylene-b-styrene) block copolymers. 788 Storey et al. also

observed that the polymers appeared brittle and mechanically weak at low rubber block

molecular weights, and high elongations were only obtained at high rubber block molecular

weights (120K).

786 Bagrodia, S.; Mohajer, Y.; Wilkes, G. L.; Storey, R. F.; Kennedy, J. P. New Polyisobutylene-Based Ionomers. 5. The Effect of Molecular Weight on the Mechanical Properties of Tri-Arm Star Polyisobutylene-Based Model Ionomers. Polymer Bulletin 1983, 9, 174-80. 787 Loveday, D.; Wilkes, G. L.; Lee, Y.; Storey, R. F. Investigation of the Structure and Properties of Polyisobutylene-Based Telechelic Ionomers of Narrow Molecular Weight Distribution. II. Mechanical. J Appl Polym Sci 1997, 63, 507-19. 788 Storey, R. F.; George, S. E.; Nelson, M. E. Star-Branched Block Copolymer Ionomers. Synthesis, Characterization, and Properties. Macromolecules 1991, 24, 2920-30.

416

0

0.1

0.2

0.3

0.4

0.5

0.6

0 50 100 150 200 250 300 350 400

Elongation (%)

Stre

ss (M

Pa)

28K20K9K4K

Figure 9.5. Tensile curves for sulfonated SEPS block copolymers.

SO3Na

SO3H

417

Table 9.2. Tensile properties of sulfonated SEPS block copolymers and fitting parameters

using model from van der Heide.

Polymer Tensile

Strength

(MPa)

Elong-

ation

(%)

Young’s

Modulus

(MPa)

Erubber

(MPa)

Ecomposite

(MPa)

Mc

(g/mol)

4K Na+ 0.29±

0.03

55±

4

0.75±

0.086

0.26±

0.025

0.91±

0.077

9000

4K H+ 0.084±

0.004

210±

55

0.24±

0.017

9K Na+ 0.25±

0.019

85±

5

0.49±

0.022

0.16±

0.013

0.58±

0.035

14000

9K H+ 0.091±

0.006

120±

15

0.27±

0.055

20K Na+ 0.48±

0.027

220±

17

0.80±

0.16

0.122±

0.009

1.09±

0.16

19000

20K H+ 0.137±

0.009

270±

70

0.35±

0.072

28K Na+ 0.31±

0.009

230±

17

0.61±

0.043

0.065±

0.002

0.83±

0.094

35000

28K H+ 0.143±

0.007

180±

50

0.56±

0.085

418

The absence of a yield point was noted in the tensile curves for the sulfonated SEPS

triblock copolymers, which indicated a lack of continuity of the hard phase.789 For the

sulfonic acid-functionalized SEPS, stress relaxation due to sample flow was observed during

the tensile experiment, leading to unexpected increases in Young’s moduli with increased

rubber block molecular weight. For the sodium sulfonated block copolymers, trends were

not observed in Young’s modulus or tensile strength. More strenuous sample drying

conditions (60 oC, vacuum, 24 h, storage over P2O5) did not alter these observations.

The tensile data were fitted using a model developed by van der Heide et al. to describe

polyurethanes, which was also subsequently applied to SBS elastomers (Figure 9.6, Table

9.2).790 This model assumes a phase separated system in which a composite modulus (Ec,

containing contributions from the hard phase as well as rubber matrix) is observed at low

strains followed by a rubber modulus (Er) at higher strains. The fitting parameters for the

sodium sulfonated block copolymers revealed a decrease in rubber modulus with increasing

rubber block molecular weight, which is a consequence of decreasing physical crosslink

density (Figure 9.7). The tensile data for the sulfonic acid-functionalized block copolymers

were not fit due to the stress relaxation that occurred during testing. The effective molecular

weight between crosslinks (Mc) for the sodium sulfonated polymers were calculated from

rubbery elasticity theory based on the rubber moduli calculated from the van der Heide

treatment. The Mc values increased with rubber block molecular weights as expected and

789 Bajaj, P.; Varshney, S.K. Morphology and mechanical properties of poly(dimethyl siloxane-b-styrene-b-dimethyl siloxane) block copolymers. Polymer, 1980, 21, 201-6. 790 van der Heide, E.; Van Asselen, O. L. J.; Ingenbleek, G. W. H.; Putman, C. A. J. Tensile Deformation Behaviour of the Polymer Phase of Flexible Polyurethane Foams and Polyurethane Elastomers. Macromol Symp 1999, 147, 127-37.

419

were similar to the rubber block molecular weights (Figure 9.7). Wilkes et al. calculated

expected values of Mc from the Young’s modulus of three-arm sulfonated polyisobutylene

telechelic ionomers.791

791 Mohajer, Y.; Tyagi, D.; Wilkes, G. L.; Storey, R. F.; Kennedy, J. P. New Polyisobutylene Based Model Ionomers. 3. Further Mechanical and Structural Studies. Polym Bull 1982, 8, 47-54.

420

Figure 9.6. Typical tensile curve and fit from the model by van der Heide.

0.000

0.050

0.100

0.150

0.200

0.250

0.300

0.350

1 1.5 2 2.5 3 3.5Elongation (lambda)

Eng

inee

ring

stre

ss (M

Pa) Raw data

fit

28K Na+

Ecomposite = 0.88 MPaErubber = 0.063 MPa

421

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0 10000 20000 30000Rubber Block Mn (g/mol)

E rub

ber

(MPa

)

0

5000

10000

15000

20000

25000

30000

35000

40000

Mc (

g/m

ol)

E

M

Figure 9.7. Trends in fitting moduli and molecular weight between crosslinks for the sodium

sulfonated SEPS polymers.

rubber

c

422

9.4.4 Rheological Studies of Sulfonated Block Copolymers

Rheological studies were performed using oscillatory shear measurements in a parallel

plate rheometer on solvent cast discs of polymers for the 5K (below the entanglement

molecular weight) and 17K (above the entanglement molecular weight) sulfonated SEPS

samples (both acid and Na+ salt forms). In the complex viscosity data, the absence of a

Newtonian regime at low frequencies and the linearity of the log viscosity versus log

frequency data suggested the presence of a physical network under the conditions studied

(Figure 9.8a). For a network, a slope of -1 for the log viscosity versus log frequency is

expected.792 For the 17K sulfonated SEPS, a slope of -0.80 was observed for the sulfonic

acid form whereas the sodium sulfonated produced a slightly higher slope of -0.84 and an

improved linear fit. For the 5K sulfonated SEPS, lower slopes of -0.69 for the sulfonic acid

and -0.72 for the sodium sulfonate form were observed. Over the frequency range studied,

the 5K samples exhibited consistently higher complex viscosities, due to the higher ionic

content and physical network density. MacKnight et al. also observed a linear plot of log

complex viscosity versus log frequency for ethylene-sodium methacrylate random

copolymers793 and Wilkes et al. observed a similar trend for excess neutralized three-arm

telechelic sulfonated polyisobutylene in which the excess neutralizing agent was thought to

contribute to the hard phase.792

The samples consistently exhibited high shear storage moduli (G’) and did not appear to

792 Bagrodia, S.; Pisipati, R.; Wilkes, G. L.; Storey, R. F.; Kennedy, J. P. Melt Rheology of Ion-Containing Polymers. I. Effect of Molecular Weight and Excess Neutralizing Agent in Model Elastomeric Sulfonated Polyisobutylene-Based Ionomers. J Appl Polym Sci 1984, 29, 3065-73. 793 Earnest, T. R.; MacKnight, W. J. Effect of Hydrogen Bonding and Ionic Aggregation on the Melt Rheology of an Ethylene-Methacrylic Acid Copolymer and its Sodium Salt. J Polym Sci: Polym Phys Edn 1978, 16, 143-57.

423

reach the terminal regime over the range of temperatures studied (-30-60 oC) (Figure 9.8b).

Kennedy et al. also observed consistently high G’ values near 105 Pa for zinc neutralized

poly(methacrylic acid-b-isobutylene-b-methacrylic acid) and found that the modulus did not

substantially decrease until 200 oC.794 The storage modulus data for the 5K SEPS samples

were substantially higher than the storage modulus data for the 17K samples over the entire

frequency range. Time-temperature superposition is often unsuccessful for random

ionomers above a critical ion content due to multiple relaxation mechanisms,795796

-797

798 however,

in our microphase separated system, the ionic domains were considered fixed, especially over

the temperature ranges studied and thus a single relaxation mechanism was dominant.

794 Fang, Z.; Wang, S.; Wang, S. Q.; Kennedy, J. P. Novel block ionomers. III. Mechanical and rheological properties. J Appl Polym Sci 2003, 88, 1516-25. 795 Eisenberg, A.; Kim, J. S., Introduction to Ionomers. John Wiley and Sons: New York, 1998. 796 Navratil, M.; Eisenberg, A. Ion Clustering and Viscoelastic Relaxation in Styrene-Based Ionomers. III. Effect of Counterions, Carboxylic Groups, and Plasticizers. Macromolecules 1974, 7, 84-9. 797 Eisenberg, A.; King, M.; Navratil, M. Secondary Relaxation Behavior in Ion-Containing Polymers. Macromolecules 1973, 6, 734-7. 798 Eisenberg, A.; Navratil, M. Ion Clustering and Viscoelastic Relaxation in Styrene-Based Ionomers. II. Effect of Ion Concentration. Macromolecules 1973, 6, 604-12.

424

1.00E+00

1.00E+01

1.00E+02

1.00E+03

1.00E+04

1.00E+05

1.00E+06

0.01 1 100 10000 1000000

ωaT

η* (P

a)

4K H4K Na20K H20K Na

1.00E+03

1.00E+04

1.00E+05

1.00E+06

1.00E+07

0.01 1 100 10000 1000000

ωaT

G' (

Pa)

4K Na4K H20K Na20K H

Figure 9.8 Complex viscosity (a) and storage modulus (b) master curves of 5K and 17K

samples (Tr = 20 oC).

a)

b)

425

9.4.5 Small Angle X-Ray Scattering Characterization

SAXS is a powerful tool for the analysis of microphase separated systems and is

sensitive to electron density fluctuations through a sample, making it useful for examining

ionomers due to the presence of nanoscale ionic aggregates. The low volume fraction of

styrene and the low degree of polymerization (DP) of the styrenic blocks in the unsulfonated

precursor materials was expected to result in the absence of microphase separation. Thus,

the unsulfonated 17K and 28K SEPS polymers did not produce a scattering maximum. The

10K SEPS sample produced a very weak scattering maximum at q* = 0.058 Å-1,

corresponding to d = 10.8 nm in real space, indicating that the volume fraction of styrene was

large enough to cause microphase separation. For the 5K SEPS sample, DSC measurements

revealed two distinct glass transition temperatures, at -53 oC and -12 oC, indicating

substantial microphase separation.

The sulfonated SEPS block copolymers all produced single maxima in the

one-dimensional scattering data. The scattering maximum arose from the partially

sulfonated polystyrene domains, which were dispersed in the hydrocarbon ethylene/propylene

matrix. The absence of higher-order peaks in the SAXS data revealed a lack of long-range

ordering in these materials. Comparisons among scattering profiles for polymers with

differing rubber block molecular weights provided some insight into the progression of the

morphology with molecular weight. The intensities of the scattering maxima for the

sulfonic acid functional polymers increased with decreasing molecular weight (Figure 9.9).

This was expected due to the increase of the sulfonated styrene volume fraction with

decreasing rubber content. Similar results were obtained by Weiss et al. when sulfonating

426

SEBS block copolymers to increasing levels.799

A second variation among the sulfonated samples is in the position of the maxima. In

the microphase separated morphology, the position of the scattering maximum yields the

average interdomain spacings, given in Table 9.3. The peak positions were obtained by

fitting the scattering intensity with a Gaussian function and a linear background over a

narrow q range encompassing the peak. The interdomain distances, which were calculated

in this manner for the sulfonated block copolymers, ranged from 10 to 14 nm, and increased

with increasing molecular weight. A similar trend was observed for the sodium sulfonated

forms. Jerome et al. observed a similar trend of interdomain spacing with molecular weight

for functionalized telechelic ionomers, where the interdomain spacing was proportional to the

root-mean-square end-to-end distance.800 Loveday et al. also observed interdomain spacings

near 10 nm for 10-20K polyisobutylene telechelic ionomers and a trend of increased

interdomain spacing with molecular weight.801 Similar interdomain spacings were observed

for 15K telechelic sulfonated polyisoprenes.802

799 Lu, X.; Steckle, W. P.; Weiss, R. A. Ionic Aggregation in a Block Copolymer Ionomer. Macromolecules 1993, 26, 5876-84. 800 Sobry, R.; Fontaine, F.; Ledent, J.; Foucart, M.; Jerome, R. Morphology of Ionic Aggregates in Carboxylato- and Sulfonato-Telechelic Polyisoprenes As Investigated by Small-Angle X-ray Scattering. Macromolecules 1998, 31, 4240-52. 801 Loveday, D.; Wilkes, G. L.; Lee, Y.; Storey, R. F. Investigation of the Structure and Properties of Polyisobutylene-Based Telechelic Ionomers of Narrow Molecular Weight Distribution. I. J Appl Polym Sci 1997, 63, 497-506. 802 Venkatshwaran, L. N.; Tant, M. R.; Wilkes, G. L.; Charlier, P.; Jerome, R. Structure-property comparison of sulfonated and carboxylated telechelic ionomers based on polyisoprene. Macromolecules 1992, 25, 3996-4001.

427

0.1

1

10

100

1000

0 0.03 0.06 0.09 0.12 0.15 0.18

q (Å-1)

Inte

nsity

(cm

-1) 9K

20K28K

Figure 9.9. 1-D SAXS profiles for sulfonated block copolymers of varying rubber block

molecular weights.

428

Table 9.3. Summary of scattering maxima position and Bragg spacing for sulfonated block

copolymers.

Rubber Block

Mn Form q* (Å-1) d (nm)

4 SO3H 0.060 10.4

4 SO3Na 0.065 9.7

9 SO3H 0.055 11.4

9 SO3Na 0.061 10.3

20 SO3H 0.049 12.6

20 SO3Na 0.053 11.9

28 SO3H 0.047 13.4

28 SO3Na 0.049 12.9

429

The SAXS spectra of the sodium sulfonated polymers featured decreased Bragg

spacings compared to the sulfonic acid polymers (Table 9.3). This was observed as a shift

in the scattering maxima to higher q upon neutralization of the polymer (Figure 9.10). The

smaller spacing between hard phases may arise from a “tightening” of the physical network

structure due to the increased attractive forces between ionic groups compared to neutral

sulfonic acid groups. Weiss observed a similar trend with oil-swollen sulfonated SEBS

which was attributed to increasing strength of association.803 Weiss and coworkers also

observed a broadening of the SAXS peak with increasing strength of association, with the

breadth increasing in the order of “precursor” < “SO3H” < “SO3Na”. Such broadening is

clearly visible in comparing the sulfonic acid containing polymers with the sodium sulfonated

ionomers (Figure 9.10). The increased peak breadth was attributed to the hindered

morphological development due to stronger interactions in the sodium sulfonated polymers.

Other researchers have observed a shift in morphology due to sulfonation, such as from

cylindrical to lamellar morphologies,804 apparently due to the increased drive for microphase

separation and the thermodynamic driving force to minimize interfacial surface area.

803 Lu, X.; Steckle, W. P.; Weiss, R. A. Morphological Studies of a Triblock Copolymer Ionomer by Small Angle X-ray Scattering. Macromolecules 1993, 26, 6525-30. 804 Balas, J. G.; Gergen, W. P.; Willis, C. L.; Pottick, L. A.; Gelles, R.; Weiss, R. A. Sulfonated block copolymers. US Patent 5239010, 1993.

430

0.1

1

10

100

1000

0 0.03 0.06 0.09 0.12 0.15 0.18

q (Å-1)

Inte

nsity

(cm

-1) SO H

SO Na

Figure 9.10. Effect of neutralization on the scattering maxima in the sulfonated block

copolymer (10K sample).

Neutralization 3

3

431

Weiss et al. have studied similar sulfonated

poly(styrene-b-ethylene-co-butylene-b-styrene) polymers and observed peaks in SAXS

arising from both block copolymer microphase separation (d = 10-30 nm) as well as from

ionic aggregation (d = 2-6 nm). Weiss et al. concluded that the ionic aggregates resided

within the microphase separated styrene domains.805 , 806 Similar ionic peaks were also

observed in Nafion™, 807 however, an ionomer peak was not observed in the present studies.

This may be due to the fact that films were prepared using solution casting, which was shown

to suppress the ionomer peak.805 Also, the high level of sulfonation was shown to shift q

values for the ionic peak above 0.2 Å-1 (for 18 mol% sulfonation), which is an angular range

that was not examined in this experiment.805

9.4.6 Atomic Force Microscopy (AFM) Characterization

Tapping mode AFM studies of the sulfonated block copolymers revealed microphase

separation at the surface, with harder sulfonated styrene domains dispersed in a soft

hydrogenated diene matrix apparent in the phase image (Figure 9.11). The smoothness and

absence of structure in the topographic images (not shown) suggested that the structure

present in the phase image indeed reflected “hard” and “soft” phases. The hard domains

appeared to exhibit a spherical morphology as would be expected for the small styrene

volume fractions. These domains are clearly not ordered in the material, corroborating the

805 Lu, X.; Steckle, W. P.; Weiss, R. A. Ionic Aggregation in a Block Copolymer Ionomer. Macromolecules 1993, 26, 5876-84. 806 Lu, X.; Steckle, W. P.; Weiss, R. A. Morphological Studies of a Triblock Copolymer Ionomer by Small Angle X-ray Scattering. Macromolecules 1993, 26, 6525-30. 807 Mauritz, K. A.; Moore, R. B. State of Understanding of Nafion. Chem. Rev 2004, 104, 4535-85.

432

lack of higher order peaks in the SAXS experiments. Similar images were obtained from

spin-coated samples and slowly evaporated films, suggesting that the rate of evaporation was

not preventing the ordering of the material. A cursory examination of the AFM images

revealed hard domain spacings close to those obtained in SAXS experiments (~12-18 nm),

however, these did not strongly correlate with rubber block molecular weight. Due to the

strength of the tapping, however, multiple layers of thickness were likely sampled

simultaneously, thereby preventing an accurate determination of the interdomain distances.

AFM characterization of the unsulfonated precursor polymers did not reveal any surface

texture.

433

Figure 9.11. Tapping mode AFM phase images of the sulfonated block copolymer series.

Each image is 1 um x 1 um. Samples were spin-coated on silicon wafers and are unannealed.

9K Na+

9K H+ 28K H+ 20K H+

20K Na+ 28K Na+

4K H+

4K Na+

250 nm 250 nm

250 nm 250 nm 250 nm

250 nm

250 nm

250 nm

434

9.5 Conclusions

Novel, short outer block sulfonated styrene-ethylene/propylene-styrene triblock

copolymers were synthesized and characterized via small angle x-ray scattering (SAXS),

dynamic mechanical analysis (DMA), tensile testing, rheology, and atomic force microscopy

(AFM). The polymers exhibited microphase separation in which the minor component,

sulfonated polystyrene formed a dispersed, hard phase in the soft, ethylene/propylene rubbery

matrix. The sulfonated polystyrene phases appeared roughly spherical in shape, and no

evidence of long-range order was observed. DMA revealed the presence of two glass

transition temperatures and increasing rubber phase Tg with molecular weight. Tensile

measurements showed increased elongation with molecular weight and higher tensile

strengths for the sodium sulfonated polymers. Rheological measurements confirmed the

presence of a non-covalent network structure. The interdomain spacing measured by SAXS

increased with rubber block molecular weight and decreased upon neutralization of the block

copolymers, suggesting a “tightening” of the network. AFM revealed phase separated

morphologies at the surface, with similar length scales of phase separation.


The authors would like to acknowledge Carl Willis and Dale Handlin of Kraton

Polymers for helpful discussions and Kraton Polymers for financial support. This material is

based upon work supported by, or in part by, the U.S. Army Research Laboratory and the U.S.

Army Research Office under grant number DAAD19-02-1-0275 Macromolecular

Architecture for Performance (MAP) MURI.

435

Chapter 10. Morphological Analysis of Telechelic Ureido-Pyrimidone

Functional Hydrogen Bonding Linear and Star-Shaped

Poly(ethylene-co-propylene)s

(Mather, B.D.; Elkins, C.L.; Beyer, F.L; Long, T.E., Macromolecular Rapid Communications,

submitted)

10.1 Abstract

Ureidopyrimidone (UPy) end-functionalized linear and star-shaped

poly(ethylene-co-propylene)s (hydrogenated polyisoprene) with molecular weights between

12K and 90K and narrow molecular weight distributions (Mw/Mn < 1.10) were synthesized

via living anionic polymerization followed by chain-end modification reactions. UPy

end-functionalized poly(ethylene-co-propylene)s of varying topology were studied with

small-angle X-ray scattering (SAXS) and atomic force microscopy (AFM). These hydrogen

bond end-functionalized polymers (0.45-1.14 mol% UPy end-groups) unexpectedly exhibited

microphase separated domains with interdomain spacings of approximately 10-15 nm

suggesting a solid-state clustering of the hydrogen bonding end-groups beyond simple

dimerization. The interdomain spacings that were obtained from SAXS measurements

systematically increased with molecular weight and decreased for monofunctional oligomers

relative to telechelic analogs of the identical molecular weight. Variable temperature AFM

measurements confirmed the presence of microphase separation at the surface for the

star-shaped UPy end-functional poly(ethylene-co-propylene) and revealed a decrease in phase

436

contrast upon heating to 130 oC with retention of the microphase separated texture.

10.2 Introduction

Multiple hydrogen bonding enables the introduction of thermoreversible linkages and

molecular recognition sites into novel macromolecular architectures through the tailoring of

specific non-covalent intermolecular interactions. 808809

-810

811 The association strength is a

function of various environmental parameters such as temperature, solvent, humidity, and pH,

and consequently, the thermomechanical and rheological properties are also controlled

through a number of environmental variables. The strength of hydrogen bonding associations

are further tunable using controlled polymerization strategies and molecular design of the

hydrogen bonding scaffold. For example, DNA nucleotide bases possess association

constants near 102 M-1 whereas synthetic quadruple hydrogen bonding ureidopyrimidone

(UPy) arrays may possess association constants as high as 107 M-1. 812

Hydrogen bonding interactions play a vital role in the development of self-assembling

supramolecular structures.813814

-815

816 Lehn et al. studied the development of helical fibers from

808 Elkins, C. L.; Viswanathan, K.; Long, T. E. Synthesis and Characterization of Star-Shaped Poly(ethylene-co-propylene) Polymers Bearing Terminal Self-Complementary Multiple Hydrogen-Bonding Sites. Macromolecules 2006, 39, 3132-9. 809 Yamauchi, K.; Kanomata, A.; Inoue, T.; Long, T. E. Thermoreversible Polyesters Consisting of Multiple Hydrogen Bonding (MHB). Macromolecules 2004, 37, 3519-22. 810 Mather, B. D.; Lizotte, J. R.; Long, T. E. Synthesis of Chain End Functionalized Multiple Hydrogen Bonded Polystyrenes and Poly(alkyl acrylates) Using Controlled Radical Polymerization. Macromolecules 2004, 37, 9331-7. 811 Yamauchi, K.; Lizotte, J. R.; Long, T. E. Synthesis and Characterization of Novel Complementary Multiple-Hydrogen Bonded (CMHB) Macromolecules via a Michael Addition. Macromolecules 2002, 35, 8745-50. 812 Sontjens, S. H. M.; Sijbesma, R. P.; van Genderen, M. H. P.; Meijer, E. W. Stability and Lifetime of Quadruply Hydrogen Bonded 2-Ureido-4[1H]-pyrimidinone Dimers. J Am Chem Soc 2000, 122, 7487-93. 813 Brunsveld, L.; Folmer, B. J. B.; Meijer, E. W.; Sijbesma, R. P. Supramolecular Polymers. Chem Rev

437

complementary difunctional Janus wedge style recognition units.817 Chiral complementary

diacyldiaminopyridine and uracil-functionalized tartaric acids demonstrated formation of

helical fibers, and the chirality of the precursors dictated the structure of the supramolecular

helix.818 Meijer et al. functionalized oligo-p-phenylenevinylenes with ureido-s-triazines,

which formed associated helical structures in dodecane.819 Rotello et al. also have observed

giant vesicles, which were created from non-covalent, reversibly crosslinked, microspheres,

and reversibly adsorbed polymer chains to surfaces through the association of

diacylaminopyridine and thymine-functionalized polystyrene.820821

- 822 Furthermore, Rotello et

al. also achieved reversible side chain functionalization using the

diacylaminopyridine/thymine recognition pair.823

2001, 101, 4071-97. 814 Hilger, C.; Drager, M.; Stadler, R. Molecular Origin of Supramolecular Self-Assembling in Statistical Copolymers. Macromolecules 1992, 25, 2498-501. 815 Lehn, J. M. Supramolecular polymer chemistry- scope and perspectives. Polym Int 2002, 51, 825-39. 816 Whitesides, G. M.; Simanek, E. E.; Mathias, J. P.; Seto, C. T.; Chin, D. N.; Mammen, M.; Gordon, D. M. Noncovalent Synthesis: Using Physical-Organic Chemistry To Make Aggregates. Acc Chem Res 1995, 28, 37-44. 817 Berl, V.; Schmutz, M.; Krische, M. J.; Khoury, R. G.; Lehn, J. M. Supramolecular Polymers Generated from Heterocomplementary Monomers Linked through Multiple Hydrogen-Bonding Arrays–Formation, Characterization, and Properties. Chem Eur J 2002, 8, 1227-44. 818 Gulik-Krzywicki, T.; Fouquey, C.; Lehn, J. M. Electron microscopic study of supramolecular liquid crystalline polymers formed by molecular-recognition-directed self assembly from complementary chiral components. Proc Natl Acad Sci USA 1993, 90, 163-7. 819 Schenning, A. P. H. J.; Jonkheijm, P.; Peeters, E.; Meijer, E. W. Hierarchical Order in Supramolecular Assemblies of Hydrogen-Bonded Oligo(p-phenylene vinylene)s. J Am Chem Soc 2001, 123, 409-16. 820 Ilhan, F.; Galow, T. H.; Gray, M.; Clavier, G.; Rotello, V. M. Giant Vesicle Formation through Self-Assembly of Complementary Random Copolymers. J Am Chem Soc 2000, 122, 5895-6. 821 Thibault, R. J.; Hotchkiss, P. J.; Gray, M.; Rotello, V. M. Thermally Reversible Formation of Microspheres through Non-Covalent Polymer Cross-Linking. J Am Chem Soc 2003, 125, 11249-52. 822 Norsten, T. B.; Jeoung, E.; Thibault, R. J.; Rotello, V. M. Specific Hydrogen-Bond-Mediated Recognition and Modification of Surfaces Using Complementary Functionalized Polymers. Langmuir 2003, 19, 7089-93. 823 Ilhan, F.; Gray, M.; Rotello, V. M. Reversible Side Chain Modification through Noncovalent

438

UPy groups exhibit unusually high association constants (6x107 M-1 in chloroform) due

to the presence of four hydrogen bonds in a configuration that minimizes repulsive

interactions between opposing hydrogen bonding groups.824,825 This DDAA configuration (D

= donor, A = acceptor) also results in self-complementary behavior, in contrast to nucleotide

bases which are complementary (A-T, G-C). The planar structure of the UPy molecule and

intramolecular hydrogen bonding assists in creating and maintaining a geometry that

maximizes hydrogen bonding (Figure 10.1). The lifetime in solution of UPy dimers was

reported as high as 170 ms in chloroform or 1.7 s in toluene.824 Meijer et al. have also

demonstrated that molecules containing two UPy groups form reversible, non-covalent,

supramolecular polymers in solution. 826 These supramolecular polymers were formed

through chain-extension resembling step-growth polymerization. Difunctional UPy

molecules, which associate intramolecularly into cyclics at room temperature, were found to

“polymerize” non-covalently via ring-opening with increased temperature.827

Interactions.“Plug and Play” Polymers. Macromolecules 2001, 34, 2597-601. 824 Sontjens, S. H. M.; Sijbesma, R. P.; van Genderen, M. H. P.; Meijer, E. W. Stability and Lifetime of Quadruply Hydrogen Bonded 2-Ureido-4[1H]-pyrimidinone Dimers. J Am Chem Soc 2000, 122, 7487-93. 825 Beijer, F. H.; Sijbesma, R. P.; Kooijman, H.; Spek, A. L.; Meijer, E. W. Strong Dimerization of Ureidopyrimidones via Quadruple Hydrogen Bonding. J Am Chem Soc 1998, 120, 6761-9. 826 Sijbesma, R. P.; Beijer, F. H.; Brunsveld, L.; Folmer, B. J. B.; Hirschberg, J. H. K. K.; Lange, R. F. M.; Lowe, J. K. L.; Meijer, E. W. Reversible Polymers Formed from Self-Complementary Monomers Using Quadruple Hydrogen Bonding. Science 1997, 278, 1601-4. 827 Folmer, B. J. B.; Sijbesma, R. P.; Meijer, E. W. Unexpected Entropy-Driven Ring-Opening Polymerization in a Reversible Supramolecular System. J Am Chem Soc 2001, 123, 2093-4.

439

N

NO

CH3

N

O

N

N

N O

CH3

N

O

N

HHHH

H

H

NH

O

O(CH2)3

Figure 10.1. Ureidopyrimidone (UPy) quadruple hydrogen bonded dimer attached to

poly(ethylene-co-propylene)s.

440

The UPy group has generated significant interest recently as efforts have transitioned

from synthesizing functional low molecular weight molecules to high molecular weight

polymers containing the UPy group. Meijer and coworkers demonstrated that

end-functionalization of 3-arm poly(ethylene oxide-co-propylene oxide) oligomers with UPy

groups converted the viscous liquid precursors into viscoelastic solids.828 The solution

viscosity of these trifunctional oligomers decreased with the addition of monofunctional UPy

“chain stoppers” and with increasing solvent polarity. Difunctional UPy functional siloxanes

exhibited degrees of non-covalent polymerization of 20-100.829 In addition, the siloxanes

exhibited endotherms in DSC measurements that were attributed to the melting of crystallites

of UPy dimers. Guan et al. have incorporated the UPy group into polyurethanes to create

intra-chain non-covalently cyclized polymers, 830 and single molecule AFM studies

demonstrated the mechanical disruption of intra-chain cyclic formations. Long and coworkers

have introduced telechelic UPy functionality into polyesters via post-polymerization

modification.831 Melt rheological studies revealed hydrogen bond dissociation temperatures

for telechelic poly(butylene isophthalate) near 80 oC and improved mechanical properties.

Coates and coworkers have introduced the UPy group into polyolefins via copolymerization

828 Lange, R. F. M.; van Gurp, M.; Meijer, E. W. Hydrogen-Bonded Supramolecular Polymer Networks. J. Polym. Sci. A: Polym. Chem 1999, 37, 3657-70. 829 Hirschberg, J. H. K. K.; Beijer, F. H.; van Aert, A. H.; Magusin, P. C. M. M.; Sijbesma, R. P.; Meijer, E. W. Supramolecular Polymers from Linear Telechelic Siloxanes with Quadruple-Hydrogen-Bonded Units. Macromolecules 1999, 32, 2696-705. 830 Guan, Z.; Roland, J. T.; Bai, J. Z.; Ma, S. X.; McIntire, T. M.; Nguyen, M. Modular Domain Structure: A Biomimetic Strategy for Advanced Polymeric Materials. J Am Chem Soc 2004, 126, 2058-65. 831 Yamauchi, K.; Kanomata, A.; Inoue, T.; Long, T. E. Thermoreversible Polyesters Consisting of Multiple Hydrogen Bonding (MHB). Macromolecules 2004, 37, 3519-22.

441

of a UPy functional α-olefin with 1-butene. 832 Dramatic improvements in tensile

performance were observed as well as much stronger dependence of solution viscosity on

concentration. Long has also developed both random copolymers.833,834 containing the UPy

moiety as well as terminally functionalized polystyrene and polyisoprene.835,836 Random

copolymers of a UPy-functionalized methacrylate monomer with 2-ethylhexymethacrylate

exhibited decreasing creep compliance with increasing UPy content. Furthermore, both

broader plateaus in moduli as a function of frequency and higher modulus in melt rheological

studies were observed. Random copolymers with n-butyl acrylate showed a linear

relationship between Tg and UPy content, as well as stronger concentration dependence of

solution viscosity compared to non-functional analogues. Telechelic functional polyisoprene

exhibited hydrogen bond dissociation near 80 oC in melt rheological experiments.

Although significant attention has been devoted to the role of the UPy hydrogen

bonding group on solution rheological performance, fewer studies have been devoted to

understanding the solid state morphological implications of multiple hydrogen bonding

groups. Recently, Meijer et al. reported the synthesis of telechelic

832 Reith, R. L.; Eaton, F. R.; Coates, W. G. Polymerization of Ureidopyrimidinone-Functionalized Olefins by Using Late-Transition Metal Ziegler-Natta Catalysts: Synthesis of Thermoplastic Elastomeric Polyolefins. Angew Chem Int Ed 2001, 40, 2153-6. 833 Elkins, C. L.; Park, T.; McKee, M. G.; Long, T. E. Synthesis and Characterization of Poly(2-ethylhexyl methacrylate) Copolymers Containing Pendant, Self-Complementary Multiple-Hydrogen-Bonding Sites. J Polym Sci Part A: Polym Chem 2005, 43, 4618-31. 834 McKee, M. G.; Elkins, C. L.; Park, T.; Long, T. E. Influence of Random Branching on Multiple Hydrogen Bonding in Poly(alkyl methacrylate)s. Macromolecules 2005, 38, 6015-23. 835 Yamauchi, K.; Lizotte, J. R.; Hercules, D. M.; Vergne, M. J.; Long, T. E. Combinations of Microphase Separation and Terminal Multiple Hydrogen Bonding in Novel Macromolecules. J Am Chem Soc 2002, 124, 8599-604. 836 Yamauchi, K.; Lizotte, J. R.; Long, T. E. Thermoreversible Poly(alkyl acrylates) Consisting of Self-Complementary Multiple Hydrogen Bonding. Macromolecules 2003, 36, 1083-8.

442

poly(ethylene-co-butylene)s with terminal UPy groups containing linear 1,6-hexylene linker

groups with either urea, urethane or no additional functionality.837 The polymers that did not

contain adjacent urea or urethane groups did not exhibit any phase texture in atomic force

microscopy (AFM) studies. However, the introduction of adjacent urea or urethane groups

resulted in additional hydrogen bonding interactions in the lateral direction. In particular,

adjacent urea groups, which form two hydrogen bonds, produced 3-dimensional stacking of

hydrogen bonding groups leading to distinct fibril-like hard phases. This combination of

different modes of hydrogen bonding led to solid-like behavior, and improved tensile

strengths and higher storage moduli in melt rheological experiments were observed for

adjacent urethane or urea UPy-functionalized oligomers. Previous work from Meijer et al.

involving UPy end-functionalized three-arm poly(ethylene oxide-co-propylene oxide)s with

an asymmetric cycloaliphatic linker and adjacent urethane groups indicated the absence of

microphase separation from SAXS analysis whereas a urea end-functional polymer without

UPy groups did exhibit a scattering maximum.838

Long and coworkers recently reported the synthesis, thermal, mechanical, and

rheological properties of UPy hydrogen bond functionalized star-shaped

poly(ethylene-co-propylene)s (hydrogenated polyisoprene)839 with urethane groups linked

837 Kautz, H.; van Beek, D. J. M.; Sijbesma, R. P.; Meijer, E. W. Cooperative End-to-End and Lateral Hydrogen-Bonding Motifs in Supramolecular Thermoplastic Elastomers. Macromolecules 2006, 39, 4265-7. 838 Lange, R. F. M.; van Gurp, M.; Meijer, E. W. Hydrogen-Bonded Supramolecular Polymer Networks. J. Polym. Sci. A: Polym. Chem 1999, 37, 3657-70. 839 Elkins, C. L.; Viswanathan, K.; Long, T. E. Synthesis and Characterization of Star-Shaped Poly(ethylene-co-propylene) Polymers Bearing Terminal Self-Complementary Multiple Hydrogen-Bonding Sites. Macromolecules 2006, 39, 3132-9.

443

through an isophorone diisocyanate-containing asymmetric cycloaliphatic linker (Figure

10.1), and the present work focuses on the effect of polymer architecture on the morphology

of these hydrogen bonding polymers. A significant difference was observed in the case of

star-shaped UPy-functionalized polymers compared to telechelic linear polymers. The

star-shaped UPy functional polymers exhibited higher Young’s moduli, persistence of high

melt viscosity to elevated temperatures (160 oC), and behaved more elastically than telechelic

linear UPy-functionalized polymers. Due to the presence of multiple (~6) UPy sites, the star

polymer was capable of forming a hydrogen bonded network. This manuscript describes the

morphology of hydrogen bonding UPy functionalized poly(ethylene-co-propylene) polymers

as a function of architecture (star-shaped vs. linear), molecular weight, and level of

functionality. The influence of these structural parameters on morphology was studied

using a combination of small-angle X-ray scattering (SAXS) and atomic force microscopy

(AFM). This is the first report of SAXS measurements on UPy-containing star shaped

polymers. SAXS is a powerful technique for characterizing microphase separated

morphologies, and in particular, SAXS has found extensive use in the characterization of

hydrogen bond containing polymer such as polyurethanes.840 In the present study, the

presence of associating sites that contain heteroatoms (N, O) provides an adequate electron

density difference with the hydrocarbon ethylene/propylene backbone, and consequently,

UPy-based hydrogen bonded macromolecules well-suited for X-ray scattering

characterization.

840 Sheth, J. P.; Unal, S.; Yilgor, E.; Yilgor, I.; Beyer, F. L.; Long, T. E.; Wilkes, G. L. A comparative study of the structure–property behavior of highly branched segmented poly(urethane urea) copolymers and their linear analogs Polymer 2005, 46, 10180-90.

444

10.3 Experimental

10.3.1 Materials

UPy end-functional poly(ethylene-co-propylene)s were synthesized previously in our

research laboratories via living anionic polymerization of isoprene followed by

hydrogenation and post-polymerization modification.841 Briefly, isoprene was polymerized

from a protected hydroxyl alkyllithium initiator, 3-(tert-butyldimethylsiloxy)-1-propyllithium.

The polymerizations were terminated with methanol (to form monofunctional polymers),

with ethylene oxide (to form telechelic polymers), or coupled with divinylbenzene (to form

star-shaped polymers). The polymers were then hydrogenated to remove unsaturation using a

nickel (II) octoate and triethylaluminum catalyst which improved the thermal stability and

prevented crosslinking during subsequent acid-catalyzed deprotection. The deprotected

hydroxyl terminated poly(ethylene-co-propylene)s were then reacted with isophorone

diisocyanate followed by 6-methylisocytosine in the presence of DMSO to produce the final

UPy-functionalized poly(ethylene-co-propylene)s.


1H NMR spectra were collected in CDCl3 at 400 MHz with a Varian Unity Spectrometer.

Glass transition and melting temperatures were determined using a Perkin-Elmer Pyris 1

cryogenic differential scanning calorimetry (DSC) at a heating rate of 20 °C/min under

nitrogen, which was calibrated using indium (mp = 156.60 ºC) and zinc (mp = 419.47 ºC).

841 Elkins, C. L.; Viswanathan, K.; Long, T. E. Synthesis and Characterization of Star-Shaped Poly(ethylene-co-propylene) Polymers Bearing Terminal Self-Complementary Multiple Hydrogen-Bonding Sites. Macromolecules 2006, 39, 3132-9.

445

Glass transition temperatures are reported as the transition midpoint during the second heat.

Molecular weights were determined at 40 ºC in THF (HPLC grade) at 1 mL/min using

polystyrene standards on a Waters 717+ Auto-sampler size exclusion chromatography (SEC)

equipped with 3 in-line 5 μm PLgel MIXED-C columns, a Waters 2410 refractive index (RI)

detector operating at 880 nm, and Wyatt Technologies miniDAWN multiple angle laser light

scattering (MALLS) detector operating at 690 nm, which was calibrated with polystyrene

standards. The refractive index increment (dn/dc) was calculated online. All molecular

weight values reported are absolute molecular weights obtained using the MALLS detector.

SEC analysis was not reliable for star-shaped UPy functional polymers, due to their

association at SEC concentrations in THF, which was verified using dynamic light scattering.

10.3.3 Small-angle X-ray Scattering (SAXS) Measurements

UPy end-functionalized poly(ethylene-co-propylene)s were dissolved in THF and cast

in Teflon molds. The films were dried in a vacuum oven and stored at -15 oC until use.

CuKα X-ray radiation was generated using a Rigaku Ultrax18 rotating anode X-ray generator

operated at 45 kV and 100 mA. A nickel filter was used to eliminate all wavelengths but the

CuKα doublet, with an average wavelength of λ = 1.542 Å. The exact beam center and the

sample-to-detector distance of approximately 1.5 m were calibrated using silver behenate.842

The 3 m camera uses 3-pinhole collimation (300, 200 and 600 μm), and a sample-to-detector

distance of approximately 1.5 m. Two-dimensional data sets were collected using a

842 Huang, T. C.; Toraya, H.; Blanton, T. N.; Wu, Y. X-Ray-Powder Diffraction Analysis of Silver Behenate, a Possible Low-Angle Diffraction Standard. J Appl Cryst 1993, 26, 180-4.

446

Molecular Metrology 2D multi-wire area detector. The data were corrected for detector

noise, sample absorption, and background scattering, followed by azimuthal averaging to

obtain intensity as a function of the scattering vector, I(q), where q = 4π·sin(θ)/λ and 2θ is the

scattering angle. The data were then placed on an absolute scale using a type 2 glassy

carbon sample 1.07 mm thick, previously calibrated at the Advanced Photon Source in the

Argonne National Laboratory, as a secondary standard. All data processing and analysis

were done using Wavemetrics IGOR Pro 5.04 software and IGOR procedures written by Dr.

Jan Ilavsky of Argonne National Laboratory.

10.3.4 Atomic Force Microscopy (AFM) Measurements

A Veeco MultiMode™ scanning probe microscope equipped with a heating/cooling

scanner and a Nanoscope IVa controller was used for tapping-mode AFM. Polymer films

were solution cast from THF and attached to metal sample discs with a special epoxy which

does not release volatiles upon heating. Samples were imaged at a set-point ratio of 0.6 at

magnifications of 1 μm x 1 μm. Veeco’s Nanosensor silicon tips having spring constants of

10-130 N/m were utilized for imaging.


10.4.1 Polymer Synthesis

Living anionic polymerization with a protected hydroxyl functional initiator enabled the

synthesis of well-defined linear, telechelic and star-shaped polymers. The subsequent

quantitative hydrogenation, deprotection of the hydroxyl group, and final telechelic

447

functionalization led to novel UPy-containing linear monofunctional, telechelic and

star-shaped polymers. 843 The molecular weight characterization of the UPy

end-functionalized poly(ethylene-co-propylene)s and the precursor polyisoprenes is

summarized in Table 10.1. 1H NMR spectroscopy allowed determination of the the extent

of UPy-functionalization, which was typically 90 to 100% for linear

poly(ethylene-co-propylene)s and 75% for star-shaped polymers. The weight fractions of

UPy hydrogen bonding groups in the polymers ranged from 0.7 to 3.0 wt% (Table 1).

Due to the strong tendency of UPy groups to dimerize, different architectures and levels

of functionality of the macromolecules were expected to produce diverse associated

structures in solution (Figure 10.2). Based on previous literature, the monofunctional linear

polymers were expected to produce a simple dimer in solution, with twice the molecular

weight of the original polymer. The dimeric hydrogen bonding association is a dynamic

equilibrium between associated and dissociated molecules, which shifts to higher association

at increased concentration. The telechelic linear polymers were expected to form extended

chains with a degree of polymerization depending on the functionality and strength of the

association as reported earlier by Meijer et al.844 Based on average functionality greater than

two, the star-shaped polymer with peripheral functionality was expected to form a

non-covalent network-like structure.

843 Elkins, C. L.; Viswanathan, K.; Long, T. E. Synthesis and Characterization of Star-Shaped Poly(ethylene-co-propylene) Polymers Bearing Terminal Self-Complementary Multiple Hydrogen-Bonding Sites. Macromolecules 2006, 39, 3132-9. 844 Sijbesma, R. P.; Beijer, F. H.; Brunsveld, L.; Folmer, B. J. B.; Hirschberg, J. H. K. K.; Lange, R. F. M.; Lowe, J. K. L.; Meijer, E. W. Reversible Polymers Formed from Self-Complementary Monomers Using Quadruple Hydrogen Bonding. Science 1997, 278, 1601-4.

448

Table 10.1. Molecular weight and molecular weight distribution of monofunctional,

telechelic, and star-shaped polyisoprenes before and after hydrogenation and UPy

functionalization.

Polymer Topology Polymer Precursor Mn

(Mw/Mn)a

UPy functional

Mn (Mw/Mn)a

Weight % UPy

Groups

12K-mono 14800 (1.04) 18800 (1.06) 1.0 Linear monofunctional

24K-mono 23000 (1.04) 22300 (1.27) 0.7

12K-telechelic 11000 (1.05) 12200 (1.10) 2.9 Linear telechelic

24K-telechelic 24300 (1.08) 19100 (1.27) 1.4

Star 90K-star 90700 (1.37) NT 1.1

a Determined using SEC at 40 ºC in THF with a MALLS detector. Precursor molecular

weights. NT = not tested due to association in SEC solvent (THF).

449

Figure 10.2. Representation of expected modes of association for different hydrogen bonding

architectures in solution.

Monofunctional

Telechelic

Star

450

10.4.2 Small-angle X-Ray Scattering Studies

The UPy end-functionalized poly(ethylene-co-propylene)s bearing terminal

functionality generated interesting scattering profiles, as shown in Figure 10.3. In general,

all samples exhibited a single scattering maximum, which suggested the presence of a

nanometer-scale structure, which was attributed to microphase separation of the hydrogen

bonding domains within the rubbery ethylene-co-propylene matrix. The presence of

microphase separation in the absence of solvent suggested UPy associations of greater than

two, which is consistent with our previous rheological and DSC studies of telechelic UPy

end-functional polyisoprenes.845 The presence of microphase separation was also consistent

with DSC measurements of these polymers, which indicated that the UPy hydrogen bonding

group did not alter the glass transition temperature.846 Mixing of the hydrogen bonding

groups into the continuous ethylene-co-propylene matrix would be expected to increase the

glass transition temperature, as previously observed for nucleobase end-functional

polymers.847 The existence of microphase separation despite the low weight fraction of

hydrogen bonding groups (0.7 to 2.9 wt%) suggested strong association of the polar UPy

groups into aggregates. In addition, Stadler and coworkers, who studied urazole hydrogen

bonding groups attached to polydiene backbones, claimed that the urazole sites microphase

845 Yamauchi, K.; Lizotte, J. R.; Hercules, D. M.; Vergne, M. J.; Long, T. E. Combinations of Microphase Separation and Terminal Multiple Hydrogen Bonding in Novel Macromolecules. J Am Chem Soc 2002, 124, 8599-604. 846 Elkins, C. L.; Viswanathan, K.; Long, T. E. Synthesis and Characterization of Star-Shaped Poly(ethylene-co-propylene) Polymers Bearing Terminal Self-Complementary Multiple Hydrogen-Bonding Sites. Macromolecules 2006, 39, 3132-9. 847 Mather, B. D.; Lizotte, J. R.; Long, T. E. Synthesis of Chain End Functionalized Multiple Hydrogen Bonded Polystyrenes and Poly(alkyl acrylates) Using Controlled Radical Polymerization. Macromolecules 2004, 37, 9331-7.

451

separated at only 3 mol% when dispersed in a non-polar rubbery matrix.848 Stadler and

coworkers also observed single SAXS peaks for urazoylbenzoic acid functionalized

polybutadiene (~0.1 Å-1) and also concluded that these resulted from interparticle scattering

from aggregates of the hydrogen bonding groups in the rubber matrix.849,850 However, in

sharp contrast to UPy functional polymers, urazoylbenzoic acid functionalized polymers, are

expected to aggregate since hydrogen bonding can occur from two sides of the molecule.

For example, 4-phenylurazole functionalized polymers, which enable only a simple

dimerization of functional groups, did not reveal SAXS maxima.849 Previous SAXS

experiments by Meijer et al. involving UPy end-functionalized three-arm poly(ethylene

oxide-co-propylene oxide)s with similar asymmetric cycloaliphatic linkers and adjacent

urethane groups indicated no evidence of microphase separation.851 The difference between

these previous observations and the present results was presumed to arise from the lower

polarity of the poly(ethylene-co-propylene) matrix compared to poly(ethylene

oxide-co-propylene oxide), leading to a greater insolubility of the UPy groups in the matrix.

848 Dardin, A.; Stadler, R.; Boeffel, C.; Spiess, H. W. Molecular dynamics of new thermoplastic elastomers based on hydrogen bonding complexes: a deuteron nuclear magnetic resonance investigation. Makromol Chem 1993, 194, 3467-77. 849 Hilger, C.; Stadler, R. Cooperative Structure Formation by Directed Noncovalent Interactions in an Unpolar Polymer Matrix. 7. Differential Scanning Calorimetry and Small-Angle X-ray Scattering. Macromolecules 1992, 25, 6670-80. 850 Hilger, C.; Stadler, R. New Multiphase Architecture from Statistical Copolymers by Cooperative Hydrogen Bond Formation. Macromolecules 1990, 23, 2095-7. 851 Lange, R. F. M.; van Gurp, M.; Meijer, E. W. Hydrogen-Bonded Supramolecular Polymer Networks. J. Polym. Sci. A: Polym. Chem 1999, 37, 3657-70.

452

0.01

0.1

1

10

0 0.05 0.1 0.15 0.2

q (Å-1)

Inte

nsity

(cm

-1)

12K mono24K mono

0.01

0.1

1

10

100

0 0.05 0.1 0.15 0.2

q (Å-1)

Inte

nsity

(cm

-1)

12K telechelic24K telechelic

Figure 10.3. SAXS data for UPy-containing monofunctional (left chart) and telechelic (right

chart) poly(ethylene-co-propylene)s polymers.

453

The hydrogen bonding polymers exhibited regular trends in the position of the

scattering maxima with respect to molecular weight and architecture. The positions of the

scattering maxima were calculated through fitting the sum of a Gaussian peak-shape and a

linear baseline to the scattering data. The positions of the maxima were then used to

determine the Bragg spacing, d = 2π/q, which corresponded to the average interdomain

spacings of 8 to 16 nm (Table 10.2). A shift in the position of the scattering maxima to lower

angles (or larger spacings) with increasing molecular weight (Figure 10.3) was observed.

Both monofunctional (12K-mono and 24K-mono) and telechelic (12K-telechelic and

24K-telechelic) UPy end-functional poly(ethylene-co-propylene)s exhibited a shifting of the

SAXS maxima to lower q with increasing molecular weight. The molecular weight between

UPy groups was presumed to correlate with the distance between UPy-rich domains in a

microphase separated morphology. Stadler et al. also observed a shifting of the SAXS

maxima for urazoylbenzoic acid functionalized polybutadiene to higher q for higher levels of

functionality (lower molecular weight between functional groups). 852 Jérôme et al.

correlated Bragg spacing with molecular weight (d ~ Mn0.5) for telechelic polyisoprene

ionomers, and similar trends with molecular weight were apparent for the present UPy

functionalized polymers.853

852 Hilger, C.; Stadler, R. Cooperative Structure Formation by Directed Noncovalent Interactions in an Unpolar Polymer Matrix. 7. Differential Scanning Calorimetry and Small-Angle X-ray Scattering. Macromolecules 1992, 25, 6670-80. 853 Sobry, R.; Fontaine, F.; Ledent, J.; Foucart, M.; Jerome, R. Morphology of Ionic Aggregates in Carboxylato- and Sulfonato-Telechelic Polyisoprenes As Investigated by Small-Angle X-ray Scattering. Macromolecules 1998, 31, 4240-52.

454

Table 10.2. Scattering maxima and corresponding Bragg spacings for UPy functional

poly(ethylene-co-propylene)s.

Polymer q* (Å-1) d (nm)

12K-mono 0.058 10.8 ± 0.1

12K-telechelic 0.078 8.1 ± 0.1

24K-mono 0.041 15.5 ± 0.1

24K-telechelic 0.059 10.7 ± 0.1

90K-star 0.074 8.5 ± 0.1

Upon further examination of the scattering data as a function of architecture, it appeared

that a transition from monofunctional linear to telechelic linear functionality resulted in a

shift of the maxima to higher angles (smaller real-space correlation distances), as illustrated

in Figure 10.4. This effect was consistently observed for samples of different molecular

weight, and was attributed to an increase in the overall concentration of hydrogen bonding

groups while maintaining the molecular weight of the polymer. Although the telechelic UPy

functional polymers did not possess perfect difunctionality (f > 1.80), their functionality was

twice that of the monofunctional UPy functional polymers (f > 0.90).

The 90K-star polymer, which contained an average of eight 12K arms, and an average

of six UPy groups due to incomplete functionalization, produced a single scattering

maximum in a similar fashion to linear monofunctional and telechelic oligomers (Figure

10.5). However, the position of this peak was at a higher q value than the positions of the

455

scattering maxima for the 12K-mono or the 24K-telechelic, which suggested an even smaller

distance between microphase separated domains of the UPy hydrogen bonding groups. The

star architecture was viewed as a collection of linear, monofunctional 12 kg/mol arms joined

together at their non-functional termini. Thus, the presence of intramolecular association is

more probable, which would also contribute to a decrease in the size of the star-shaped

polymer. Future efforts will involve modeling the scattering behavior of the UPy-containing

polymers with models such as the Yarusso-Cooper model, in order to better understand the

morphology of these unique polymers.854,855

854 Benetatos, N. M.; Heiney, P. A.; Winey, K. I. Reconciling STEM and X-ray Scattering Data from a Poly(styrene-ran-methacrylic acid) Ionomer: Ionic Aggregate Size. Macromolecules 2006, 39, 5174-6. 855 Yarusso, D. J.; Cooper, S. L. Microstructure of Ionomers: Interpretation of Small-Angle X-ray Scattering Data. Macromolecules 1983, 16, 1871-80.

456

0.01

0.1

1

10

100

0 0.05 0.1 0.15 0.2

q (Å-1)

Inte

nsity

(cm

-1)

12K mono12K telechelic

Figure 10.4. SAXS data showing the effect of functionality for 12 kg/mol polymers.

457

0.01

0.1

1

10

0 0.05 0.1 0.15 0.2

q (Å-1)

Inte

nsity

(cm

-1)

12K mono90K star

Figure 10.5. Scattering profile for star-shaped poly(ethylene-co-propylene) with UPy

functional periphery and the 12K monofunctional polymer.

458

10.4.3 Atomic Force Microscopy

Tapping mode AFM studies were performed on the UPy end-functional

poly(ethylene-co-propylene)s. It is well established that tapping mode AFM allows for

detailed analysis of the surface morphology as well as topography. 856 The UPy

functionalized 90K star-shaped polymer was the only sample which clearly revealed a surface

texture that was indicative of microphase separation (Figure 10.6). Numerous solvent

casting procedures and annealing procedures were performed with the linear samples and a

microphase separated surface texture was not observed. For the star-shaped architecture, it

was proposed that the hard phases were less mobile in the rubbery ethylene-co-propylene

matrix due to the central connection point in the star topology. Meijer et al. have also

observed the absence of microphase separation on the surfaces of telechelic UPy functional

poly(ethylene-co-butylene)s.857 In the case of urethane or urea groups bonded to the UPy

functionality through symmetric 1,6-hexylene linkers, fibril-like surface textures were

observed due to the lateral stacking of the urea groups, which differed strikingly from the

images of the present star-shaped poly(ethylene-co-propylene). The differences observed in

the AFM images of the present system, which also contains urethane groups, was proposed to

arise from the asymmetry of the isophorone diisocyanate linker, which presumably prevents

stacking of the urethane groups.

856 Maganov, S. N., Atomic Force Microscopy in Analysis of Polymers. In Encyclopedia of Analytical Chemistry, Meyers, R. A., Ed. John Wiley and Sons: Chichester, UK, 2000; pp 7432-91. 857 Kautz, H.; van Beek, D. J. M.; Sijbesma, R. P.; Meijer, E. W. Cooperative End-to-End and Lateral Hydrogen-Bonding Motifs in Supramolecular Thermoplastic Elastomers. Macromolecules 2006, 39, 4265-7.

459

The phase image of the 90K star-shaped polymer exhibited 10-15 nm hard phases

dispersed in a rubbery matrix. Typical interdomain distances as measured using AFM were

10-20 nm, although the spacing was not regular and long-range ordering was not apparent.

Due to the low UPy content in the star polymer (1.1 wt%), the morphology was expected to

consist of dispersed domains consisting of UPy groups. The 90K star-shaped polymer was

subjected to variable temperature AFM in order to probe the structure of the hard phases upon

dissociation of the hydrogen bonding groups (Figure 10.6). Interestingly, the hard phases

persisted to 130 oC, which was the limit of our experimental temperature range, however, the

phase contrast and apparent sizes of the hard phases both diminished significantly. Our

laboratories have shown earlier that UPy associations contribute to the rheological behavior

in the melt at elevated temperature.858 The melting phenomena of the double helical DNA

molecule has provided a paradigm for tunable intermolecular interactions.859 More recently,

similar well-defined hydrogen bond dissociation or “melting” was observed in solution

studies of synthetic adenine and thymine functionalized acrylic polymers.860 Stadler et al.

also observed the temperature sensitivity of hydrogen bonded structures in urazoylbenzoic

acid functionalized polybutadiene using variable temperature SAXS.861

858 McKee, M. G.; Elkins, C. L.; Park, T.; Long, T. E. Influence of Random Branching on Multiple Hydrogen Bonding in Poly(alkyl methacrylate)s. Macromolecules 2005, 38, 6015-23. 859 Haq, I.; Chowdhry, B. Z.; Chaires, J. B. Singular value decomposition of 3-D DNA melting curves reveals complexity in the melting process. Eur Biophys J 1997, 26, 419-26. 860 Lutz, J. F.; Thunemann, A. F.; Rurack, K. DNA-like "Melting" of Adenine- and Thymine-Functionalized Synthetic Copolymers. Macromolecules 2005, 38, 8124-6. 861 Hilger, C.; Stadler, R. Cooperative Structure Formation by Directed Noncovalent Interactions in an Unpolar Polymer Matrix. 7. Differential Scanning Calorimetry and Small-Angle X-ray Scattering. Macromolecules 1992, 25, 6670-80.

460

Figure 10.6. Variable temperature tapping mode AFM images of the UPy star-shaped polymer.

Each image is calibrated to the same phase range and measures 750 nm per side.

70 oC50 oC25 oC

90 oC 110 oC 130 oC

250 nm250 nm250 nm

250 nm 250 nm 250 nm

461

10.5 Conclusions

UPy end-functional poly(ethylene-co-propylene)s were found to form microphase

separated morphologies as determined from small-angle X-ray scattering studies. The

maxima in the SAXS data arose from interdomain scattering from the microphase separated

UPy-rich domains within the ethylene-co-propylene hydrocarbon matrix. The presence of

microphase separated domains in these polymers suggested an aggregation of the hydrogen

bonding groups beyond simple dimerization, which would not produce a clear scattering peak

in SAXS. The Bragg spacings corresponding to the scattering maxima followed trends with

molecular weight and molecular architecture. Specifically, increased molecular weight

between UPy groups lead to an increased spacing between domains, and increased

functionality of telechelic polymers lead to decreased spacings between microphase separated

domains. Variable temperature AFM revealed a decrease in phase contrast with heating to 130

oC.





462

Chapter 11. Real-time Monitoring of Molecular Recognition of

Complementary Ionic Guest Molecules with Hydrogen Bonding

Block Copolymers Using Quartz-Crystal Microbalance with

Dissipation (QCM-D)

11.1 Abstract

The molecular recognition between a water-soluble uracil functionalized phosphonium

salt and an adenine containing block copolymer poly(9-vinylbenzyladenine-b-n-butyl

acrylate-b-9-vinylbenzyladenine) surface was studied using quartz crystal microbalance with

dissipation (QCM-D) measurements. Adsorption experiments revealed a frequency drop of

17.6 Hz associated with the adsorption. The uracil phosphonium salt was not completely

rinsed from the surface with water, suggesting strong specific recognition. Control

experiments with non-nucleobase containing poly(styrene-b-n-butyl acrylate-b-styrene) block

copolymers revealed a frequency drop of 8.8 Hz, which was nearly completely reversible

upon rinsing with water. X-ray crystallographic analysis of the uracil phosphonium salt

revealed the competitive hydrogen bonding of water with the uracil group, which may play a

role in the adsorption measurements.

463

11.2 Introduction

Hydrogen bonding enables the introduction of thermoreversible properties into


Recent interest in hydrogen bonding in both supramolecular863 and macromolecular864

design has inspired numerous new explorations. The strength of hydrogen bonding

interactions is highly dependent on temperature, solvent, humidity and pH, thus allowing

control of the degree of association through a number of environmental parameters.

Nucleobases, which exhibit association strengths near 100 M-1, are ideal for introducing

dynamic hydrogen bonding interactions into polymers.865 Rowan et al. noted that the

behavior of the isolated nucleobases in synthetic polymers is quite different from their

behavior in DNA where they are bound to a complementary base. 866 Multiple

complementary association modes are possible for nucleobases, including the classical

Watson-Crick mode which is present in DNA as well as the less commonly observed

Hoogsteen association mode. 867 Furthermore, nucleobases exhibit several weak

862 Yamauchi, K.; Lizotte, J. R.; Hercules, D. M.; Vergne, M. J.; Long, T. E. Combinations of Microphase Separation and Terminal Multiple Hydrogen Bonding in Novel Macromolecules. J Am Chem Soc 2002, 124, 8599-604. 863 Brunsveld, L.; Folmer, B. J. B.; Meijer, E. W.; Sijbesma, R. P. Supramolecular Polymers. Chem Rev 2001, 101, 4071-98. 864 Ilhan, F.; Galow, T. H.; Gray, M.; Clavier, G.; Rotello, V. M. Giant Vesicle Formation through Self-Assembly of Complementary Random Copolymers. J Am Chem Soc 2000, 122, 5895-6. 865 Kyogoku, Y.; Lord, R. C.; Rich, A. The Effect of Substituents on the Hydrogen Bonding of Adenine and Uracil Derivatives. Proc Natl Acad Sci USA 1967, 57, 250-7. 866 Sivakova, S.; Bohnsak, D. A.; Mackay, M. E.; Suwanmala, P.; Rowan, S. J. Utilization of a Combination of Weak Hydrogen-Bonding Interactions and Phase Segregation to Yield Highly Thermosensitive Supramolecular Polymers. J Am Chem Soc 2005, 127, 18202-18211. 867 Ghosal, G.; Muniyappa, K. Hoogsteen base-pairing revisited: Resolving a role in normal biological processes and human diseases. Biochemical and Biophysical Research Communications 2006, 343, 1-7.

464

self-association modes (Ka<10 M-1),865 which compete with the complementary association

modes.

Complementary hydrogen bonding interactions facilitate the introduction of guest

molecules containing complementary recognition units. Others have shown the recognition of

guest molecules through hydrogen bonding interactions in both solution868 and the solid

state. 869 Rotello et al. have used three-point hydrogen bonding between

diacyldiaminopyridines and thymine to attach guest molecules containing flavin870 or POSS

to polystyrene.869 Rotello has also used hydrogen bond functional polymers to reversibly

attach polymers on surfaces, 871 and reversibly attach functional small molecules on

polymers.872 Ten Brinke et al. studied the blending of alkyl substituted phenols on poly(vinyl

pyridine).873 Guest molecules can also increase the solubility of hydrogen bonding polymers,

maintaining homogeneity during polymerization reactions.874 We recently reported on the

introduction of phosphonium ionic guest molecules into hydrogen bonding block copolymers

868 Thibault, R. J.; Hotchkiss, P. J.; Gray, M.; Rotello, V. M. Thermally Reversible Formation of Microspheres through Non-Covalent Polymer Cross-Linking. J Am Chem Soc 2003, 125, 11249-11252. 869 Carroll, J. B.; Waddon, A. J.; Nakade, H.; Rotello, V. M. “Plug and Play” Polymers. Thermal and X-ray Characterizations of Noncovalently Grafted Polyhedral Oligomeric Silsesquioxane (POSS)-Polystyrene Nanocomposites. Macromolecules 2003, 36, 6289-6291. 870 Ilhan, F.; Galow, T. H.; Gray, M.; Clavier, G.; Rotello, V. M. Giant Vesicle Formation through Self-Assembly of Complementary Random Copolymers. J Am Chem Soc 2000, 122, 5895-5896. 871 Norsten, T. B.; Jeoung, E.; Thibault, R. J.; Rotello, V. M. Specific Hydrogen-Bond-Mediated Recognition and Modification of Surfaces Using Complementary Functionalized Polymers. Langmuir 2003, 19, 7089-93. 872 Ilhan, F.; Gray, M.; Rotello, V. M. Reversible Side Chain Modification through Noncovalent Interactions. "Plug and Play" Polymers. Macromolecules 2001, 34, 2597-601. 873 Valkama, S.; Ruotsalainen, T.; Kosonen, H.; Ruokolainen, J.; Torkkeli, M.; Serimaa, R.; ten Brinke, G.; Ikkala, O. Amphiphiles Coordinated to Block Copolymers as a Template for Mesoporous Materials. Macromolecules 2003, 36, 3986-3991. 874 Stubbs, L. P.; Weck, M. Towards a Universal Polymer Backbone: Design and Synthesis of Polymeric Scaffolds Containing Terminal Hydrogen-Bonding Recognition Motifs at Each Repeating Unit. Chem Eur J 2003, 9, 992-9.

465

with concomitant changes in morphology and physical properties.875

The quartz crystal microbalance (QCM) technique is a powerful technique for

monitoring surface adsorption due to the high sensitivity of the quartz crystal to adsorbed

mass. Recently, dissipative measurements of the oscillation have been coupled with QCM,

allowing a measure of changes in viscous losses on the surface of the crystal. Hook et al.

recently demonstrated the application of the quartz crystal microbalance technique to

hydrogen bonding systems in the study of adsorption of DNA oligobases to complementary

surface-anchored PNA.876 QCM has also found applications in biological systems, where

recognition of antibodies and proteins can be studied.877 The sensitivity of the QCM

technique is typically very high, allowing detection of very small amounts of adsorbed mass,

even allowing detection of gases.878

In this manuscript, we discuss the molecular recognition of an adenine-containing

surface with a complementary uracil-containing phosphonium salt (Figure 11.1). In DNA,

hydrogen bonding and π-stacking interactions hold the double helix together, despite

repulsive interactions between the phosphate ionic backbones. This is an inspiration for the

875 Mather, B. D.; Baker, M. B.; Beyer, F. L.; Green, M. D.; Berg, M. A. G.; Long, T. E. Multiple Hydrogen Bonding for the Reversible Attachment of Ionic Functionality in Block Copolymers. Macromolecules 2007, Submitted. 876 Hook, F.; Ray, A.; Norden, B.; Kasemo, B. Characterization of PNA and DNA Immobilization and Subsequent Hybridization with DNA Using Acoustic-Shear-Wave Attenuation Measurements. Langmuir 2001, 17, 8305-12. 877 Hook, F.; Rodahl, M.; Brzezinski, P.; Kasemo, B. Energy Dissipation Kinetics for Protein and Antibody-Antigen Adsorption under Shear Oscillation on a Quartz Crystal Microbalance. Langmuir 1998, 14, 729-34. 878 Pasquinet, E.; Bouvier, C.; Thery-Merland, F.; Hairault, L.; Lebret, B.; Methivier, C.; Pradier, C. M. Synthesis and adsorption on gold surfaces of a functionalized thiol: elaboration and test of a new nitroaromatic gas sensor. J Coll Int Sci 2004, 272, 21-7.

466

current work, in which hydrogen bonds reversibly connect strongly interacting ionic

molecules to a neutral polymer backbone.

467

Figure 11.1. Molecular recognition of uracil containing phosphonium salt with complementary

hydrogen bonding block copolymer.

EtO

OEtO

O

OBuO

O OBu

nnn n

N

N

N

N

NN

H2N

N

N

N

NHO

N

OP

Cl

HH

H

Adenine polymer

Aqueous solution

468

11.3 Experimental

11.3.1 Materials



N-tert-butyl-N-(1-diethylphosphono-2,2-dimethylpropyl)-N-oxyl (DEPN) nitroxide, 879

DEPN2,880 UPPh3+ 881 and 9-vinylbenzyl adenine882 were synthesized according to the

previous literature.

11.3.2 Polymerization of n-Butyl Acrylate from DEPN2

DEPN2 alkoxyamine (212 mg, 0.269 mmol) and DEPN nitroxide (31 mg, 0.105 mmol)

were weighed into a 100-mL round-bottomed flask containing a magnetic stirbar. The flask

was sealed with a three-way joint allowing introduction of reagents via syringe and

application of vacuum and nitrogen. The flask was evacuated to 60 mtorr and refilled with

high-purity nitrogen three times. Purified n-butyl acrylate (30 mL, 209 mmol) was added via

syringe and the mixture was degassed with three freeze-pump-thaw cycles. Finally, the flask

was immersed in an oil bath thermostated at 122 oC for 3 h. After the polymerization, residual

879 Grimaldi, S.; Finet, J. P.; Le Moigne, F.; Zeghdaoui, A.; Tordo, P.; Benoit, D.; Fontanille, M.; Gnanou, Y. Acyclic B-Phosphonylated Nitroxides: A New Series of Counter-Radicals for "Living"/Controlled Free Radical Polymerization. Macromolecules 2000, 33, 1141-7. 880 Mather, B. D.; Baker, M. B.; Beyer, F. L.; Green, M. D.; Berg, M. A. G.; Long, T. E. Multiple Hydrogen Bonding for the Reversible Attachment of Ionic Functionality in Block Copolymers. Macromolecules 2007, Submitted. 881 Klein, R. S.; Fox, J. J. Nucleosides. LXXVIII. Synthesis of Some 6- Substituted Uracils and Uridines by the Wittig Reaction. J Org Chem 1972, 37, 4381-6. 882 Srivatsan, S. G.; Parvez, M.; Verma, S. Modeling of Prebiotic Catalysis with Adenylated Polymeric Templates: Crystal Structure Studies and Kinetic Characterization of Template-Assisted Phosphate Ester Hydrolysis. Chem. Eur. J. 2002, 8, 5184-91.

469

monomer was removed in vacuo (60 mtorr, 40 oC, 6 h). SEC analysis in THF revealed

molecular weight data Mn = 16500, Mw/Mn = 1.24.

11.3.3 Synthesis of Adenine Containing Block Copolymer

Poly(n-butyl acrylate) homopolymer (4.83 g, Mn = 16500, Mw/Mn = 1.24) and

9-vinylbenzyladenine (0.99 g, 3.9 mmol) were added to a 50-mL round-bottomed flask with a

magnetic stirbar. The flask was sealed with a three-way joint and evacuated to 60 mtorr and

refilled with high-purity nitrogen three times. DMF (15 mL) was then syringed into the flask

and the mixture was degassed with three freeze-pump-thaw cycles. The flask was then

immersed in an oil bath at 122 oC for 5 h. After the polymerization, the polymer was isolated

via precipitation into methanol. 1H NMR (DMSO-d6) revealed block molecular weights

A1.5K-nBA16.5K-A1.5K. 1H NMR (400 MHz, DMSO-d6, 25 °C) (δ, ppm): 0.86 (t, CH3, 3H) 1.30

(q, COOCH2CH2CH2CH3, 2H), 1.5 (br, CH2-CH-COO and COOCH2CH2-), 1.75 (br,

CH2-CH-COO-, 1H), 2.2 (br, CH-COO-, 1H), 4.0 (br, COOCH2, 2H), 5.2 (br, Ph-CH2, 2H),

6.3 (br, Ph, 2H), 6.9 (br, Ph, 2H), 7.6 (br, NH2, 2H), 8.1 (br, adenine ring protons, 2H).

11.3.4 Synthesis of Poly(styrene-b-n-butyl acrylate-b-styrene) Block Copolymer

Poly(n-butyl acrylate) homopolymer (155 mg, Mn = 23,700, Mw/Mn = 1.11) and styrene

(5 mL, 43 mmol) were added to a 50-mL round-bottomed flask with a magnetic stirbar. The

flask was sealed with a three-way joint and the solution was degassed with three

freeze-pump-thaw cycles. The flask was then immersed in an oil bath at 120 oC for 40 min.

After the polymerization, the polymer was isolated via precipitation into methanol. 1H

470

NMR (CDCl3) revealed block molecular weights S14.6K-nBA23.7K-S14.6K. SEC measurements

in THF revealed a molecular weight of Mn = 48400, Mw/Mn = 1.12 (MALLS).


Size exclusion chromatography (SEC) was performed at 40 °C in HPLC grade

tetrahydrofuran at 1 mL/min using a Waters size-exclusion chromatographer equipped with




standards. All reported molecular weight values are absolute molecular weights obtained

using the MALLS detector. 1H NMR spectroscopic data was collected in CDCl3 on a Varian

400 MHz spectrometer at ambient temperature. A Veeco MultiMode™ scanning probe

microscope was used for tapping-mode AFM. Polymer films were solution cast from

chloroform on silicon. Samples were imaged at a set-point ratio of 0.6 at magnifications of

500 nm x 500 nm. Veeco’s Nanosensor silicon tips having spring constants of 10-130 N/m

were utilized for imaging. X-ray data was collected on an Oxford Diffraction XcaliburTM

diffractometer equipped with a SapphireTM 3 CCD detector. The data collection routine, unit

cell refinement, and data processing were carried out with the program CrysAlis(v1.171,

Oxford Diffraction: Wroclaw, Poland, 2004). Structure solution and refinement were

performed with the graphical user interface WinGX.883 The structures were solved by direct

883 Farrugia, L. J. WinGX: An Integrated System of Windows Programs for the solution, Refinement and Analysis of Single X-ray Diffraction Data. J Appl Cryst 1999, 32, 837-8.

471

methods using SHELXS-97884 and refined using SHELXL-97. The final refinement model

involved anisotropic displacement parameters for non-hydrogen atoms and a riding model for

all hydrogens. The program package ORTEP-3 was used for molecular graphic generation.885

11.3.6 Quartz Crystal Microbalance with Dissipation (QCM-D) Measurements

Quartz crystal microbalance measurements were performed on a Q-Sense E4 operating

in 7th overtone on AT-cut quartz crystals with gold electrodes with a fundamental frequency

of 4.97 MHz. The instrument possessed a normal mass adsorption sensitivity of 3.5 ng/cm2

and a maximum sensitivity of 1 ng/cm2. The measurements were conducted at 25 oC at a

flow rate of 150 uL/min. All aqueous solutions were prepared from Millipore water. Exposure

to UPPh3+ was conducted with solutions of 0.5 wt% concentration. Data analysis was

performed using QTools software. The bare quartz sensor crystals were cleaned prior to use

by exposure to UV/ozone for 10 min, followed by rinsing with water and drying with

nitrogen. Polymer films were deposited on the wafers by spin-coating at 3000 rpm from

chloroform solution at 0.37 wt% concentration. The sample was then dried annealed at 155

oC under vacuum.


11.4.1 Synthesis of Nucleobase Functional Hydrogen Bonding Block Copolymers

A novel, difunctional alkoxyamine initiator based on DEPN nitroxide, denoted DEPN2,

884 Sheldrick, G. M. SHELX97. Programs for Crystal Structure Analysis. University of Gottingen, Gottingen, 1997. 885 Farrugia, L. J. ORTEP-3 for Windows - a version of ORTEP-III with a Graphical User Interface (GUI). J Appl Cryst 1997, 30, 565.

472

was synthesized via conventional copper-promoted atom transfer radical addition techniques

from a commercially available dihalide precursor.886 Adenine hydrogen bonding groups

were introduced via a nucleobase-containing styrenic monomers, and 9-vinylbenzyladenine

(Figure 11.2). The residual monomers and solvent were removed via precipitation into

methanol, yielding purified polymer products. 1H NMR spectroscopy was used to verify the

presence of the nucleobases and to quantify the degree of polymerization of the outer blocks,

based on the known poly(n-butyl acrylate) rubber block molecular weights that were

determined from SEC in THF. The block molecular weights were A1.5K-nBA16.5K-A1.5K. SEC

was also carried out on the nucleobase functional block copolymers in THF, revealing narrow

molecular weight distributions and monomodal traces for the final triblock copolymers.

However, SEC was not suitable for the determination of hydrogen bonding block molecular

weights due to the relatively short block lengths.

886 Matyjaszewski, K.; Woodworth, B. E.; Zhang, X.; Gaynor, S.; Metzner, Z. Simple and Efficient Synthesis of Various Alkoxyamines for Stable Free Radical Polymerization. Macromolecules 1998, 31, 5955-7.

473

EtOO

OOEt

O OnBu

DEPN

OOnBu

DEPNn n

EtOO

OOEt

O OnBu

OOnBu

n nDEPN

DEPN

mm

9-vinylbenzyl adenine

120 oC

N

N

NN

H2N

N

N

NN

NH2

DMF

Figure 11.2. Synthesis of hydrogen bonding triblock copolymers containing adenine and

thymine nucleobases from difunctional DEPN terminated poly(n-butyl acrylate).

474

11.4.2 Quartz Crystal Microbalance Measurements

The adenine containing block copolymer was spin coated onto the quartz crystal

microbalance crystal with the gold electrodes. The polymer layer was annealed at 155 oC

under vacuum to allow the development of morphology as observed using AFM (Figure 11.3).

The hard domains at the surface (light color) suggest the accessibility of the adenine

functional groups to solutions introduced to the film. SAXS measurements on this polymer

previously established a cylindrical morphology.887 The spin-coated polymer film thickness

(δfilm) was estimated from the frequency change (Δf) using the Sauerbrey equation:888

fm nC

filmfilmQCM Δ==Δ δρ [11.1]

where ρfilm is the density of the film, CQCM is an instrument constant (17.7 ng/cm2Hz), and n

is the overtone number (Table 11.1). The film thickness estimated from the seventh overtone

was 133 nm. Cross-sectional SEM measurements yielded a film thickness value of 127 nm,

confirming the result from SEM. A control polymer, consisting of poly(styrene-b-n-butyl

acrylate-b-styrene) (S14.6K-nBA23.7K-S14.6K) was also spin-coated onto a quartz crystal,

yielding a film thickness of 73 nm.

887 Mather, B. D.; Baker, M. B.; Beyer, F. L.; Green, M. D.; Berg, M. A. G.; Long, T. E. Multiple Hydrogen Bonding for the Reversible Attachment of Ionic Functionality in Block Copolymers. Macromolecules 2007, Submitted. 888 Sauerbrey, G. The use of quartz oscillators for weighing thin layers and for microweighing. Z. Phys. 1959, 155, 206-22.

475

Table 11.1. Film thickness of adenine containing polymer using QCM and SEM.

Surface Δf /n (Hz) QCM

Thickness (nm)

SEM

Thickness (nm)

Adenine Polymer -782 133 127

Control -407 73 -

476

Figure 11.3. Tapping mode AFM a) height and b) phase images of adenine containing

polymer spin coated on Si, from chloroform solution. Annealing was performed at 155 oC

under vacuum for 18 h. Film thickness ~ 100 nm. Images are 1 um x 1 um. Full color

variation corresponds to a 10 nm change in height (a) or 10 degrees of phase (b).

250 nm 250 nm

a) b)

477

The adenine polymer coated quartz crystal was first exposed to humid air, in order to

monitor the weight uptake due to moisture. The adenine-containing polymer surface adsorbed

45 ng/cm2 of water almost immediately upon the exposure to the film to humid air (Figure

11.4, Table 11.2). In contrast, the control polymer exhibited nearly no change upon exposure

to humid air. Both polymer surfaces were carefully kept dry prior to measurement, through

storage in desiccator after drying in a vacuum oven at 155 oC. The greater water adsorption

by the adenine containing polymer film was expected due to the polar, hydrogen bonding

nature of the adenine functional groups. In contrast, the control polymer consisted of

comparatively non-polar constituents (styrene and n-butyl acrylate).

478

-20

0

20

40

60

80

100

0 100 200 300 400 500 600time (s)

Δm

ng/

cm2

AdenineControl

Figure 11.4. Changes in frequency (7th overtone) with exposure to humid air, 25 oC.

479

Table 11.2. Effect of moisture uptake on frequency and dissipation of adenine containing

polymer and control polymer.

Surface Δm (ng/cm2) Δf/n (Hz) Moisture ΔD Moisture

(x10-6)

Adenine Polymer 45 -2.7 -0.04

Control -2 +0.2 +0.28

480

Exposure of the adenine-containing polymer to the complementary uracil-containing

phosphonium salt (UPPh3+) was conducted by introducing the phosphonium salt in an

aqueous solution (0.5 wt%). This required the previous exposure of the film to water. The

frequency change observed upon introduction of UPPh3+ (-17.6 Hz) corresponded to a mass

uptake of 317 ng/cm2. Upon rinsing with pure Millipore water, the uracil-containing

phosphonium salt was partially desorbed (-289 ng/cm2). The control polymer adsorbed

UPPh3+ to a lower extent (157 ng/cm2) than the adenine containing polymer. Furthermore,

upon rinsing, the control polymer lost the majority of the phosphonium salt (-152 ng/cm2).

The greater adsorption and retention of the phosphonium salt by the adenine containing

polymer was attributed to the complementary hydrogen bonding interaction.

The incomplete loss of UPPh3+ upon rinsing was thought to possibly arise from the

permeation of the guest molecule into the bulk of the film. During the adsorption step

(Figure 11.5), the weight uptake of the adenine-containing polymer continues gradually after

an initial large change (~260 ng/cm2). This may be attributed to permeation into the bulk of

the film, whereas the initial weight uptake may represent rapid adsorption at the surface.

Since the adenine containing polymer possesses a cylindrical morphology, there may be some

continuity of the hard phases, which would facilitate permeation through these hard domains.

Changes in the dissipation of the films were similar between the adenine containing polymer

and the control polymer, during the UPPh3+ adsorption step (Table 11.3). The increase in

dissipation is commonly observed with increased mass adsorption.

Hook et al. studied the adsorption of single stranded complementary or

481

single-mismatched DNA oligobases (15 bp) to PNA to surface.889 Hook observed higher

levels of adsorption of the fully complementary DNA as well as greater retention upon

rinsing with buffer solutions. These results were consistent with those observed in the current

study.

889 Hook, F.; Ray, A.; Norden, B.; Kasemo, B. Characterization of PNA and DNA Immobilization and Subsequent Hybridization with DNA Using Acoustic-Shear-Wave Attenuation Measurements. Langmuir 2001, 17, 8305-12.

482

0

50

100

150

200

250

300

350

0 200 400 600 800 1000 1200 1400time (s)

Δm

(ng/

cm2 )

Adenine polymer

Control

Figure 11.5. Changes in frequency (7th overtone) with exposure to UPPh3+ in water (0.5 wt%),

25 oC for adenine-containing and control block copolymer.

483

Table 11.3. Adsorption of UPPh3+ on adenine-containing and control block copolymers.

Adsorption (UPPh3+) Rinsing (H2O) Surface

Δm

(ng/cm2)

Δf/n (Hz) ΔD

(x10-6)

Δm

(ng/cm2)

Δf/n (Hz) ΔD

(x10-6)

Adenine Polymer 317 -17.6 0.96 -289 +16.1 -1.01

Control 157 -8.8 0.97 -152 +8.6 -0.51

484

11.4.3 X-ray Crystallographic Studies of Uracil Phosphonium Salt

X-ray crystallography was carried out on the uracil-containing phosphonium salt

(UPPh3+) for the first time. Crystallization experiments were conducted in ethanol, which

yielded a crystal structure in which thymine hydrogen bonding groups were dimerized

through hydrogen bonding interactions (Figure 11.6). The distances between the carbonyl

oxygens (O1) and hydrogen bonded nitrogens (N3) on the opposite uracil were 2.81 Å in

each case. Uracil possesses a weak hydrogen bonding dimerization constant (Ka = 6 M-1).890

Ethanol was also observed in the crystal structure as disordered solvent and was not observed

to hydrogen bond to the uracil group or to disrupt the dimerization. The chloride counterion

was weakly hydrogen bonded to the uracil N1-H (3.11 Å, N to Cl distance) while maintaining

a position relatively close to the phosphonium center (P to Cl distance 4.22 Å).

890 Kyogoku, Y.; Lord, R. C.; Rich, A. The Effect of Substituents on the Hydrogen Bonding of Adenine and Uracil Derivatives. Proc Natl Acad Sci USA 1967, 57, 250-7.

485


crystallized from ethanol. Solvent molecules and hydrogens are omitted for clarity.

486

Crystallization of the phosphonium salt from a mixture of water and THF resulted in the

incorporation of one water molecule hydrogen bonded to the uracil N3-H (Figure 11.7, 2.81

Å, O to N distance). The water hydrogens were also hydrogen bonded to chloride counterions

on neighboring molecules (3.19 Å, O to Cl distance). As in the structure of UPPh3+ crystals

from ethanol, the chloride counterion was hydrogen bonded to the uracil N1-H (3.16 Å, N to

Cl distance) and the distance to the phosphonium center was similar (4.31 Å, P to Cl). The

strong hydrogen bonding capabilities of water were sufficient to disrupt the dimerization of

the uracil groups. This hydrogen bond screening ability of water was thought to be

responsible for the ability to remove UPPh3+ from the adenine containing polymer film via

rinsing. It is remarkable, however, that UPPh3+ showed preferential adsorption to the adenine

containing polymer despite the presence of water. Others have observed decreased hydrogen

bonding association constants in the presence of water.891

891 Söntjens, S. H. M.; Sijbesma, R. P.; van Genderen, M. H. P.; Meijer, E. W. Stability and Lifetime of Quadruply Hydrogen Bonded 2-Ureido-4[1H]-pyrimidinone Dimers. J Am Chem Soc 2000, 122, 7487-93.

487


crystallized from water/THF. Hydrogens omitted for clarity.

488

11.5 Conclusions

The molecular recognition between a water-soluble uracil functionalized phosphonium

salt and an adenine containing block copolymer poly(9-vinylbenzyladenine-b-n-butyl

acrylate-b-9-vinylbenzyladenine) surface was studied using quartz crystal microbalance with

dissipation (QCM-D) measurements. Adsorption experiments revealed a frequency drop of

17.6 Hz associated with the adsorption. The uracil phosphonium salt was not completely

rinsed from the surface with water, suggesting strong specific recognition. Control

experiments with non-nucleobase containing poly(styrene-b-n-butyl acrylate-b-styrene) block

copolymers revealed a frequency drop of 8.8 Hz, which was nearly completely reversible

upon rinsing with water. X-ray crystallographic measurements of the uracil phosphonium

salt revealed the competitive hydrogen bonding of water with the uracil group, which may

play a role in the adsorption measurements.

11.6 Acknowledgement




489

Chapter 12. Introduction of Central Diester Functionality in

Polystyrenes Using Living Radical Polymerization for Graft Polyester

Synthesis

12.1 Abstract

Novel, central diester functional polystyrenes were synthesized using nitroxide

mediated polymerization from a difunctional alkoxyamine initiator (DEPN2). The thermal

stability of the functional polystyrenes was improved through the removal of the DEPN

nitroxide end-groups, which was achieved through heating in the presence of thiol containing

compounds. The removal of DEPN was confirmed with NMR spectroscopy and improved

thermal stability was observed with TGA. The polystyrene diesters were then introduced into

high temperature melt polyesterification reactions. The resultant polyester graft copolymers

had polystyrene contents that were close to charged levels 2.5-10 wt%.

12.2 Introduction

Nitroxide mediated polymerization has gained attention recently as a technique for

synthesizing narrow polydispersity linear and block copolymers with controlled molecular

weights.892 The use of unimolecular alkoxyamine initiators has increased in recent years,

due to the control over the ratio of initiator to nitroxide as well as the possibility for

892 Hawker, C.; Bosman, A.; Harth, E. New Polymer Synthesis by Nitroxide Mediated Living Radical Polymerizations. Chemical Reviews 2001, 101, 3661-88.

490

introduction of functionality onto the polymer chain end.893,894

Recently, our group has developed a difunctional alkoxyamine initiator, DEPN2, which

facilitates the synthesis of triblock copolymers by reducing the number of crossover steps

compared to sequential polymerization and ensuring symmetric outer blocks.895 The DEPN2

initiator also benefits from a continuous carbon chain, which prevents potential hydrolysis

found in other difunctional initiators.896 Finally, the DEPN2 initiator also introduces two ester

functional groups into the center of the synthesized polymers.

Graft copolymers have unique molecular architecture which is tunable via a variety of

parameters including arm molecular weight, graft density and composition. The unique

architecture of graft copolymers results in novel rheological behavior.897,898 Graft copolymers

have found utility in gene transfection,899 drug delivery and controlled release,900,901 and in

893 Gavranovic, G.; Csihony, S.; Bowden, N.; Hawker, C.; Waymouth, R.; Moerner, W.; Fuller, G. Well-Controlled Living Polymerization of Perylene-Labeled Polyisoprenes and Their Use in Single-Molecule Imaging. Macromolecules 2006, 39, 8121 -7. 894 Mather, B.; Lizotte, J.; Long, T. Synthesis of Chain End Functionalized Multiple Hydrogen Bonded Polystyrenes and Poly(alkyl acrylates) Using Controlled Radical Polymerization. Macromolecules 2004, 37, 9331-7. 895 Mather, B.; Long, T. Supramolecular triblock copolymers containing complementary molecular recognition. PMSE Preprints 2006, 95, 304-5. 896 Robin, S.; Guerret, O.; Couturier, J.; Pirri, R.; Gnanou, Y. Synthesis and Characterization of Poly(styrene-b-n-butyl acrylate-b-styrene) Triblock Copolymers Using a Dialkoxyamine as Initiator. Macromolecules 2002, 35, 3844-8. 897 Hempenius, M.; Zoetelief, W.; Gauthier, M.; Moller, M. Melt Rheology of Arborescent Graft Polystyrenes Macromolecules 1998, 31, 2299 -2304. 898 Krishnamoorti, R.; Giannelis, E. Strain Hardening in Model Polymer Brushes under Shear Langmuir 2001, 17, 1448 -52. 899 Unger, F.; Wittmar, M.; Kissel, T. Branched polyesters based on poly[vinyl-3- (dialkylamino)alkylcarbamate-co-vinyl acetate-co-vinyl alcohol]-graftpoly(D,L-lactide-co-glycolide): Effects of polymer structure on cytotoxicity. Biomaterials 2007, 28, 1610-9. 900 Lo, C.-L.; Huang, C.-K.; Lin, K.-M.; Hsiue, G.-H. Mixed micelles formed from graft and diblock copolymers for application in intracellular drug delivery. Biomaterials 2007, 28, 1225-35. 901 Gref, R.; Rodrigues, J.; Couvreur, P. Polysaccharides Grafted with Polyesters: Novel Amphiphilic Copolymers for Biomedical Applications. Macromolecules 2002, 35, 9861-7.

491

the modification of biopolymers such as chitosan,902 dextran903 or cellulose derivatives904 to

alter the hydrophilicity and impart unique solubility characteristics or for biomedical

applications. Further applications exist in membranes for removal of heavy metals from

wastewater.905

Graft copolymers are typically synthesized via one of several approaches: grafting to a

preformed backbone using radical initiators,906 radiation,907 or linking chemistry,908 grafting

from a macroinitiator,904909

- 910a polymer containing multiple initiation sites, and finally

(co)polymerization of a macromonomer,911912

- 913 a low molar mass polymer (typically Mn <

902 Joshi, J.; Sinha, V. Ceric ammonium nitrate induced grafting of polyacrylamide onto carboxymethyl chitosan. Carbohydrate Polymers 2007, 67, 427-35. 903 Li, Y.; Volland, C.; Kissel, T. Biodegradable brush-like graft polymers from poly(D,L-lactide) or poly(D,L-lactide-co-glycolide) and charge-modified, hydrophilic dextrans as backbone-in-vitro degradation and controlled releases of hydrophilic macromolecules. Polymer 1998, 39, 3087-97. 904 Kang, H.; Liu, W.; He, B.; Shen, D.; Ma, L.; Huang, Y. Synthesis of amphiphilic ethyl cellulose grafting poly(acrylic acid) copolymers and their self-assembly morphologies in water. Polymer 2006, 47, 7927-34. 905 Okieimen, F. E.; Sogbaike, C. E.; Ebhoaye, J. E. Removal of cadmium and copper ions from aqueous solution with cellulose graft copolymers. Separation and Purification Technology 2005, 44, 85-9. 906 Russell, K. Free radical graft polymerization and copolymerization at higher temperatures. Prog Polym Sci 2002, 27, 1007-38. 907 Nasef, M.; Hegazy, E.-A. Preparation and applications of ion exchange membranes by radiation-induced graft copolymerization of polar monomers onto non-polar films. Prog Polym Sci 2004, 29, 499-561. 908 Parrish, B.; Emrick, T. Aliphatic Polyesters with Pendant Cyclopentene Groups: Controlled Synthesis and Conversion to Polyester-graft-PEG Copolymers. Macromolecules 2004, 37, 5863-5. 909 Li, H.; Zhao, H.; Zhang, X.; Lu, Y.; Hu, Y. A novel route to the synthesis of PP-g-PMMA copolymer via ATRP reaction initiated by Si–Cl bond. Eur Polym J 2007, 43, 109-18. 910 Chung, T. Synthesis of functional polyolefin polymers with block and graft architectures. Prog Polym Sci 2002, 27, 39-85. 911 Lahitte, J.; Plentz-Meneghetti, S.; Peruch, F.; Isel, F.; Muller, R.; Lutz, P. Design of new styrene enriched polyethylenes via coordination copolymerization of ethylene with mono- or α,ω-difunctional polystyrene macromonomers. Polymer 2006, 47, 1063-72. 912 Mespouille, L.; Degee, P.; Dubois, P. Amphiphilic poly(N,N-dimethylamino-2-ethyl methacrylate)-g-poly(ε-caprolactone) graft copolymers: synthesis and characterisation. Eur Polym J 2005, 41, 1187-95. 913 Sato, M.; Mangyo, T.; Mukaida, K. Thermotropic liquid-crystalline aromatic

492

10000) containing a polymerizeable functional group. The macromonomer approach, which

will be the focus of this manuscript, benefits from well-defined graft lengths and avoids the

potential side reactions possible with the “grafting-to” approach. The synthesis of

macromonomers is typically achieved using living polymerization techniques and they may

be incorporated using radical polymerization,912 coordination polymerization911 or

condensation routes.913 Recently, even “click chemistry” was applied to the synthesis of graft

copolymers.914,915

Living radical polymerization possesses the advantage of producing grafts with

well-defined lengths. Living radical polymerization gained attention recently as a useful tool

for the synthesis of graft copolymers.916 For instance, ATRP was used to graft PMMA onto

a silyl chloride functionalized polypropylene.917 ATRP was also utilized to graft poly(acrylic

acid) side chains onto ethyl cellulose via an esterification with a haloacid halide.918 The

macromonomer approach has also been utilized with controlled radical polymerization.

Dubois et al. utilized ATRP to copolymerize a methacrylate-terminated poly(ε-caprolactone)

polyester-graft-poly(2,6-dimethyl-l,4-phenylene oxide) copolymers. Macromol. Chem. Phys. 1995, 196, 1791-9. 914 Riva, R.; Schmeits, S.; Jerome, C.; Jerome, R.; Lecomte, P. Combination of Ring-Opening Polymerization and “Click Chemistry”: Toward Functionalization and Grafting of Polycaprolactone. Macromolecules 2007, 40, 796-803. 915 Parrish, B.; Breitenkamp, R.; Emrick, T. PEG- and Peptide-Grafted Aliphatic Polyesters by Click Chemistry. J Am Chem Soc 2005, 127, 7404-10. 916 Davis, K.; Matyjaszewski, K., Advances in Polymer Science, 159. Statistical, Gradient, Block and Graft Copolymers by Controlled/Living Radical Polymerizations. Springer-Verlag: New York, 2002; p 192. 917 Li, H.; Zhao, H.; Zhang, X.; Lu, Y.; Hu, Y. A novel route to the synthesis of PP-g-PMMA copolymer via ATRP reaction initiated by Si-Cl bond. Eur Polym J 2007, 43, 109-18. 918 Kang, H.; Liu, W.; He, B.; Shen, D.; Ma, L.; Huang, Y. Synthesis of amphiphilic ethyl cellulose grafting poly(acrylic acid) copolymers and their self-assembly morphologies in water. Polymer 2006, 47, 7927-34.

493

with N,N-dimethylaminoethyl methacrylate to make amphiphilic graft copolymers.919 ATRP

was also used to synthesize centrally difunctional aryl dibromide macromonomers to make

poly(phenylene) graft copolymers. 920 Relatively few works utilize nitroxide mediated

polymerization for graft copolymer synthesis. Nitroxide mediated polymerization was also

used in the synthesis of graft copolymer. For example, an alkoxyamine containing

diphenylacetylene monomer was polymerized using coordination catalysis and was then used

as a macroinitiator to polymerize styrene.921 Also, nitroxides were used to mediate the

polymerization of styrene from Barton ester functionalized poly(arylene ether sulfone)s.922

Polyesters have novel properties due to their biodegradability, potential crystallinity and

recyclability. Graft polyesters have advantages in terms of the potential to create

biodegradable amphiphilic molecules with potential drug delivery application.923 In the case

of graft polyesters, macromonomers possessing alcohol or ester groups may be incorporated.

Graft polyesters were prepared in melt polycondensation with dicarboxyterminated

poly(2,6-dimethyl-1,4-phenylene oxide).924 In this report, we describe a route to centrally

functionalized diester containing polystyrenes synthesized using nitroxide mediated

919 Mespouille, L.; Degee, P.; Dubois, P. Amphiphilic poly(N,N-dimethylamino-2-ethyl methacrylate)-g-poly(ε-caprolactone) graft copolymers: synthesis and characterisation. Eur Polym J 2005, 41, 1187-95. 920 Cianga, I.; Yagci, Y. New polyphenylene-based macromolecular architectures by using well defined macromonomers synthesized via controlled polymerization methods. Prog Polym Sci 2004, 29, 387-99. 921 Miura, Y.; Okada, M. Synthesis of densely grafted copolymers by nitroxide-mediated radical polymerization of styrene using poly(phenyl acetylene)s as a macroinitiator. Polymer 2004, 45, 6539-46. 922 Daly, W.; Evenson, T. Grafting of vinyl polymers to carboxylated poly(arylene ether sulfone) utilizing Barton ester intermediates and nitroxide mediation. Polymer 2000, 41, 5063-71. 923 Li, Y.; Volland, C.; Kissel, T. Biodegradable brush-like graft polymers from poly(D,L-lactide) or poly(D,L-lactide-coglycolide) and charge-modified, hydrophilic dextrans as backbone-in-vitro degradation and controlled releases of hydrophilic macromolecules. Polymer 1998, 39, 3087-97. 924 Sato, M.; Mangyo, T.; Mukaida, K. Thermotropic liquid-crystalline aromatic polyester graft-poly(2,6-dimethyl-l,4-phenylene oxide) copolymers. Macromol. Chem. Phys. 1995, 196, 1791-9.

494

polymerization. These centrally functionalized polystyrenes possess narrow molecular weight

distributions and controlled molecular weights and are suitable for incorporation in graft

copolyesters or copolyamides or potentially, mikto-arm star polymers.

12.3 Experimental

12.3.1 Materials

Styrene monomer (Aldrich, 99%) was deinhibited prior to use via passage over alumina

followed by distillation from calcium hydride under reduced pressure. 1-dodecanethiol (98%),

dimethyl adipate (98%), 1,4-cyclohexanedimethanol (~30% cis/ 70% trans mixture) (99%),

antimony (III) oxide (99%) and diphenylsulfone (97%) were obtained from Aldrich and used

as received. 1,6-hexanediol (99%) was obtained from Avocado chemicals and was used as

received. Titanium (IV) isopropoxide (97%) was obtained from Aldrich and was diluted

with n-butanol to 0.01 g Ti/mL. DEPN2 initiator was synthesized according to our previously

reported procedure.925

12.3.2 Polystyrene Diester Synthesis

DEPN2 initiator (150 mg, 0.19 mmol), and styrene (5 mL, 43 mmol) were combined in

a 100-mL round-bottomed flask containing a magnetic stirbar. The flask was fitted with a

3-way joint allowing the introduction of nitrogen and the application of vacuum. The mixture

was degassed by several freeze-pump-thaw cycles and immersed in an oil bath at 125 oC for 2

925 Mather, B.; Long, T. Supramolecular triblock copolymers containing complementary molecular recognition. PMSE Preprints 2006, 95, 304-5.

495

h with stirring. The product was isolated through precipitation in methanol and was dried in a

vacuum oven at 60 oC for 18 h. The conversion of the reaction was measured using 1H NMR

of the crude reaction product, through comparing the aromatic peaks with the olefin

resonances. The conversion was determined at 32%, which enabled a calculation of the target

molecular weight (Mn,theo = 7500). SEC revealed molecular weights of Mn,actual = 6400,

Mw/Mn = 1.23. 1H NMR, CDCl3 (δ, ppm) 4.5-5.1 (br m, 2H, Ph-CH-O-N), 3.6-4.4 (br m, 12

H, OCH2CH3), 2.5-3.4 (br m, 8H, alkylene linker + CHP=O), 1.05 (br s, PO(CH2CH3)2, 12H),

0.91 (br, COOCH2CH3, 6H), 0.73 (br, CC(CH3)3, 18H), 0.59 (s, NC(CH3)3, 18H).

12.3.3 Removal of DEPN from Polystyrene Diester

Polystyrene diester (Mn = 5000, Mw/Mn = 1.45) (1.18 g, 0.23 mmol) was weighed into a

100-mL round bottomed flask containing a magnetic stirbar. 1-dodecanethiol (0.611 g, 3.0

mmol) was added along with DMF (13 mL) and the mixture was degassed, followed by

heating at 130 oC for 4 h. The product was isolated by precipitation into methanol and was

dried in a vacuum oven at 60 oC for 18 h. SEC revealed molecular weights of Mn = 5700,

Mw/Mn = 1.41.

12.3.4 Graft Polyester Synthesis

Polystyrene diester after DEPN removal (Mn = 5700, Mw/Mn = 1.41) (200 mg, 0.035

mmol), 1,6-hexanediol (3.73 g, 31.6 mmol), dimethyl adipate (5.00 g, 28.7 mmol),

diphenylsulfone (3.0 g, 13.8 mmol) and titanium tetraisopropoxide (0.05 mL, 0.01 g Ti/mL,

to achieve 60 ppm Ti) were combined in a 100-mL round-bottomed flask fitted with a

496

mechanical stirrer. The mixture was flushed with argon, and degassed with vacuum. The

transparent mixture was heated to 200 oC for 2 h, then the temperature was raised to 220 oC

for 3 h. Finally, the temperature was raised to 250 oC and vacuum was applied (30 min),

resulting in distillation of the diphenylsulfone onto the flask walls and partial precipitation of

the polystyrene diester. The reaction mixture was cooled and the polyester was dissolved in

chloroform and precipitated in diethyl ether (5x), thereby removing any unreacted

polystyrene diester, which was soluble in diethyl ether. The product was dried under vacuum

at 60 oC for 18 h. 1H NMR revealed that the graft polyester contained 2.5 wt% polystyrene.

SEC analysis of the graft polyester revealed molecular weights of Mn = 33600, Mw/Mn = 1.94.

Based on the polystyrene content and graft molecular weight, on average there was one

polystyrene diester graft for every 6.8 polyester molecules.

A polystyrene graft polyester was synthesized containing a higher content of

polystyrene diester. This polymer was synthesized with a mixture of 1,6-hexanediol and

cis/trans-1,4-cyclohexanedimethanol in order to improve solubility of the polystyrene in the

reaction mixture and attempt to create an amorphous polyester matrix. Thus, polystyrene

diester after DEPN removal (Mn = 5700, Mw/Mn = 1.41) (432 mg, 0.076 mmol),

1,6-hexanediol (1.20 g, 10.2 mmol), dimethyl adipate (2.50 g, 14.4 mmol), diphenylsulfone

(2.1 g, 9.7 mmol) 1,4-cyclohexanedimethanol (0.81 g, 5.6 mmol, mixture of cis/trans) and

titanium tetraisopropoxide (0.025 mL, 0.01 g Ti/mL, to achieve 60 ppm Ti) were combined in

a 100-mL round-bottomed flask fitted with a mechanical stirrer. The mixture was flushed

with argon, and degassed with vacuum. The transparent mixture was heated to 200 oC for 3 h,

and the temperature was raised to 220 oC for 3 h. Finally, antimony (III) oxide (200 ppm) and

497

additional diphenylsulfone (2.0 g, 9.2 mmol) were added and the temperature was raised to

250 oC for 1.5 h and finally vacuum was applied (20 min), resulting in distillation of the

diphenylsulfone out of the reaction and partial precipitation of the polystyrene diester. The

reaction mixture was cooled and the graft polyester was dissolved in chloroform and

precipitated in diethyl ether (5 x), thereby removing any unreacted polystyrene diester, which

was soluble in diethyl ether. The product was dried under vacuum at 60 oC for 18 h. 1H NMR

revealed that the graft polyester contained 4.8 wt% polystyrene and a 42 mol% incorporation

of 1,4-cyclohexanedimethanol (relative to diol content). SEC analysis of the graft polyester

revealed molecular weights of Mn = 13700, Mw/Mn = 1.35. Based on this analysis, on average

there was one polystyrene diester graft for every 8.7 polymer molecules.


1H and 31P NMR spectra were collected using a Varian Inova spectrometer operating at

400 and 162 MHz, respectively. Thermogravimetric analysis (TGA) was performed under a

nitrogen atmosphere at a heating rate of 10 °C/min using a TA Instruments Hi-Res TGA 2950.

Differential scanning calorimetry was conducted on a TA Instruments Q1000 at a heating rate

of 20 oC/min under a nitrogen purge. Size exclusion chromatography (SEC) of the

polystyrene diesters was performed on a Waters 2690 chromatographer in THF at a flow rate

of 1 mL/min at 22 oC with a T60A Viscotek Dual detector comprised of both a laser

diffractometer and a viscometer which were calibrated using polystyrene standards. Size

exclusion chromatography (SEC) of the graft polyesters was performed at 40 °C in THF at a

flow rate of 1 mL/min using a Waters size exclusion chromatographer equipped with an

498

autosampler, three 5 μm PLgel Mixed-C columns, a Waters 2410 refractive index (RI)

detector operating at 880 nm, and a miniDAWN multiangle laser light scattering (MALLS)

detector operating at 690 nm, which was calibrated with polystyrene standards. A Veeco

MultiMode™ scanning probe microscope was used for tapping-mode AFM imaging.

Samples were imaged at a set-point ratio of 0.6 at magnifications of 1 um x 1 um. Veeco’s

Nanosensor silicon tips having spring constants of 10-130 N/m were utilized for imaging.


12.4.1 Synthesis of DEPN-Terminated Polystyrene Diesters

Nitroxide mediated polymerization allows controlled molecular weight and produces

polymers with narrow polydispersity while enabling both block and graft copolymers. The

polystyrenes with central diester (termed polystyrene diesters) functionality were synthesized

in a single step using nitroxide mediated polymerization from a difunctional alkoxyamine

initiator (DEPN2) (Figure 12.1). The polystyrene diesters possessed similar appearance to

polystyrenes synthesized using other techniques. A range of polystyrene molecular weights

was obtained through varying the concentration of the initiator in the polymerization, while

maintaining similar levels of conversion (Table 12.1).

499

EtO

OEt

DEPNDEPN

O

OEtO

OEtO

O

DEPN DEPNn

nStyrene

120 oC

Figure 12.1. Synthesis of polystyrene diesters from DEPN2 initiator.

500

Table 12.1. Molecular weight characterization of polystyrene diesters.

Polystyrene diesters -

DEPN

After DEPN removalTarget

Mn a

Conversion

(%)b

Mn c Mw/Mn Mn c Mw/Mn

1st weight

loss (TGA)

(wt%)

4800 35 5000 1.45 5700 1.41 5.4

7600 32 6400 1.23 n/a n/a 4.3

14200 32 15100 1.41 15500 1.36 3.5

a Based on conversion and initiator concentration

b Conversion (1H NMR)

c Size exclusion chromatography (THF), RI detector

501

12.4.2 Removal of DEPN End-groups from Polystrene Diesters

In order to introduce the polystyrene diesters into a high temperature melt

polyesterification, the DEPN end groups, which possessed potentially reactive phosphate

esters required removal. This was achieved through heating the polystyrene diesters in the

presence of 1-dodecanethiol, a well known chain transfer reagent, which served to donate its

labile hydrogens to the polystyrene radicals that would form in the reaction (Figure 12.2).

After the reaction, the polystyrene was easily isolated through precipitation in methanol. The

removal of DEPN was verified with 1H NMR (Figure 12.3), which revealed the loss of

resonances attributed to the tert-butyl and methyl groups on DEPN. Further evidence came

from 31P NMR, which demonstrated the absence of phosphorus after the reaction (Figure

12.4). Improvements in thermal stability were observed in TGA measurements, which

indicated that the initial weight loss attributed to DEPN was absent in the DEPN-removed

polystyrene diesters (Figure 12.5). There was no evidence of side reactions with the central

ester functionality and NMR resonances corresponding to the ester functional groups (3.6-4.2

ppm) were still present in the product. Furthermore, molecular weights and distributions did

not change significantly upon DEPN removal (Table 12.1). For instance a polystyrene

diester with Mn = 5000 and Mw/Mn = 1.45 was chromatographed with SEC after DEPN

removal and exhibited Mn = 5700 and Mw/Mn = 1.41.

502

EtO

OEt

O

O

DEPNDEPN

nn

EtO

OEt

O

O

HH

nn

1-dodecanethiol

4 h 130 oCDMF

Figure 12.2. Removal of DEPN endgroups via heating with 1-dodecanethiol.

503

Figure 12.3. 1H NMR spectrum of polystyrene diester (a) after removal of DEPN (b). (Mn =

5700 after removal)

a)

b)

DEPN t-Bu DEPN

CH

504

Figure 12.4. 31P NMR data showing loss of DEPN from polystyrene diester (a) after reaction

with 1-dodecanethiol (b). (Mn = 5000)

a)

b)

505

0

20

40

60

80

100

0 200 400 600 800Temperature (oC)

Wei

ght (

%)

After reactionBefore Reaction

Figure 12.5. TGA data showing loss of DEPN endgroup and concomitant increased thermal

stability after reaction with 1-dodecanethiol for polystyrene diester (Mn = 5000 g/mol).

506

12.4.3 Synthesis of Graft Copolymers

In order to synthesize polyester graft copolymers containing the polystyrene diesters,

melt polymerization was employed. A non-polar aliphatic polyester backbone consisting of

1,6-hexanediol and dimethyl adipate was chosen to favor solubility of the polystyrene

diesters. A solvent, diphenylsulfone was necessary, to allow the polystyrene diesters to

remain soluble in the reaction medium. The lowest molecular weight polystyrene diester (Mn

= 5700 g/mol, after DEPN removal) was utilized in the reaction to maximize the

concentration of reactive ester groups. A slight excess (10 mol%) of 1,6-hexanediol monomer

was introduced into the reaction, in order to favor reaction of the polystyrene diesters. The

reaction was conducted over several hours using a temperature program typically employed

with melt polyesters.926 During the final stage of the reaction, vacuum was employed to

remove any unreacted 1,6-hexanediol. This also resulted in the loss of the diphenylsulfone

solvent, resulting in some cloudiness, due to precipitation of unreacted polystyrene. After

cooling, the polyester graft copolymer was dissolved in chloroform and precipitated 5 times

into diethyl ether, a solvent which dissolved the low molecular weight polystyrene diesters.

After this purification step, the product was analyzed with 1H NMR spectroscopy, revealing a

2.5 wt% incorporation of polystyrene, which was close to the targeted level of incorporation

(3.0 wt%). Due to the low content of polystyrene diester, the product polyester resembled

poly(hexylene adipate), and which possesses a melting point of 58 oC.927

926 Lin, Q.; Unal, S.; Fornof, A. R.; Armentrout, R. S.; Long, T. E. Synthesis and characterization of telechelic phosphine oxide polyesters and cobalt(II) chloride complexes. Polymer 2006, 47, 4085-93. 927 Brandrup, J.; Immergut, E. H., Polymer Handbook. 3rd ed.; Wiley: New York, 1989.

507

EtO

OEtO

O

H Hn

n O O OO

O

n

n

O

dimethyl adipate1,6-hexanediolTi(iOPr)4

diphenylsulfone200 oC 2 h220 oC 3 h250 oC 30 min+vacuum

O

O

Figure 12.6. Synthesis of graft polyester containing polystyrene arms.

508

Figure 12.7. 1H NMR spectrum of polyester graft copolymer (400 MHz, acetone-d6).

509

EtO

OEtO

O

H Hn

n O O O

O

O

n

n

O

dimethyl adipate1,4-cyclohexanedimethanol1,6-hexanediolTi(iOPr)4

diphenylsulfone200 oC 3 h220 oC 3 h250 oC 1.5 h+vacuum

O

O

R R

R =

Figure 12.8. Graft polyester synthesis involving 1,4-cyclohexanedimethanol (cis/trans

mixture).

510

Graft polyesters with a greater level of polystyrene incorporation (4.8 wt%, 5700 g/mol

arms) were also synthesized (Figure 12.8). These polymers also contained

1,4-cyclohexanedimethanol (35 mol% of diol content, ~30% cis / 70% trans mixture) which

decreased the level of crystallinity in the samples. However, a slow crystallization was

evident at room temperature due to the low glass transition temperature (-51 oC). A melting

temperature of 26 oC was observed with DSC. Atomic force microscopy was utilized to

study the microphase separation in these systems. AFM phase images revealed a disordered

multiphase morphology as shown in Figure 12.9. The polystyrene grafts were expected to

microphase separate from the polyester backbone. Although graft copolymers typically

exhibit less organized morphologies compared to block copolymers, some examples have

shown well-ordered morphologies, for instance poly(methyl methacrylate-g-dimethylsiloxane)

synthesized by McGrath et al.928

928 Smith, S. D.; DeSimone, J. M.; Huang, H.; York, G.; Dwight, D. W.; Wilkes, G. L.; McGrath, J. E. “Synthesis and characterization of poly(methyl methacrylate)-g-poly(dimethylsiloxane)copolymers. I. Bulk and surface characterization.” Macromolecules 1992, 25, 2575-81.

511

Figure 12.9. AFM a) height and b) phase images of a graft polyester with polystyrene arms Mn

= 5700 g/mol.

250 nm 250 nm

a) b)

512

12.5 Conclusion

A series of polystyrene diesters were synthesized using nitroxide mediated

polymerization from a difunctional alkoxyamine initiator, DEPN2. The polystyrene diesters

were thermally treated in the presence of 1-dodecanethiol to remove the DEPN endgroups.

This improved the thermal stability of the polystyrenes and removed potentially reactive

phosphonate ester functional groups. The polystyrene diesters were introduced into a melt

polyesterification, resulting in graft copolyesters containing polystyrene arms. The graft

polyesters exhibited microphase separation in AFM images.





513

Chapter 13. Future Directions - Introduction of Chiral Hydrogen

Bonding Guest Molecules for Influence of Tacticity of Radical

Polymerizations

13.1 Abstract

Hydrogen bonding monomers containing nucleobases (1-vinylthymine and

1-vinylbenzylthymine) were synthesized and polymerized in the presence or absence of

complementary (adenine) hydrogen bonding derivatives possessing chirality. The influence of

the chiral auxiliary guests on the tacticity of the polymers was analyzed by 1H NMR

spectroscopy. Polymerization of thymine-containing monomers in the presence of an

acylated, chiral adenosine derivative yielded thymine containing polymers with similar 1H

NMR spectra to those obtained for radical polymerizations conducted in the absence of the

chiral auxiliary. Analogous experiments with 1-vinylthymine produced similar results.

13.2 Introduction

Controlling the tacticity of radical polymerizations has presented a long-standing

challenge for synthetic polymer chemists. Free radical polymerizations generally produce

atactic polymers due to the symmetry of the sp2 radical propagating chain end and the

typically equal probability of reaction on either face.929 Stereocontrol is more commonly

929 Pino, P.; Sutter, U. W. Some aspects of stereoregulation in the stereospecific polymerization of vinyl monomers. Polymer 1976, 17, 977-95.

514

afforded in the case of ionic or coordination polymerization.930 In cases of vinyl monomers

with bulky substituents, radical polymerizations may result in some degree of syndiotacticity,

due steric interactions between neighboring substituents.929 This is hypothesized to cause

increased syndiotacticity in the polymerization of styrene conducted at lower temperatures.931

The tacticity of radical polymerizations may be influenced through the use of chiral

monomers.932,933

The tacticity of radical polymerizations may also be altered through the use of species

that associate reversibly or coordinate to substituents present on the polymer repeat units.

Okamoto et al. observed the influence of Lewis acidic rare earth ions (Y, Sc, Yb) on the

tacticity of acrylamide and alkylacrylamide polymerizations.934 Kamigaito et al. recently

demonstrated the combination of metal catalyzed polymerization with stereocontrol via

Lewis acids such as Y(OTf)3 to influence the tacticity of N,N-dimethylacrylamide

polymerizations.935 The coordination of the yttrium ions to neighboring amide substituents

resulted in a tendency toward isotacticity (m/r = 82/12). Royles and Sherrington have used

930 Rodriguez-Delgado, A.; Chen, E. Y. X. Mechanistic Studies of Stereospecific Polymerization of Methacrylates Using a Cationic, Chiral ansa-Zirconocene Ester Enolate. Macromolecules 2005, 38, 2587-94. 931 Standt, U.; Klein, J. On the Stereoregularity of Radically Polymerized Polystyrene. Makromol Chem Rapid Comm 1981, 2, 41-45. 932 Porter, N. A.; Allen, T. R.; Breyer, R. A. Chiral Auxiliary Control of Tacticity in Free Radical Polymerization. J Am Chem Soc 1992, 114, 7676-83. 933 Green, M. M.; Park, J.-W.; Sato, T.; Teramoto, A.; Lifson, S.; Selinger, R. L. B.; Selinger, J. V. The Macromolecular Route to Chiral Amplification. Angew. Chem. Int. Ed. 1999, 38, 3138-54. 934 Isobe, Y.; Fujioka, D.; Habaue, S.; Okamoto, Y. Efficient Lewis Acid-Catalyzed Stereocontrolled Radical Polymerization of Acrylamides. J Am Chem Soc 2001, 123, 7180-1. 935 Sugiyama, Y.; Sato, K.; Kamigaito, M.; Okamoto, Y. Iron-catalyzed radical polymerization of acrylamides in the presence of Lewis acid for simultaneous control of molecular weight and tacticity. J Polym Sci, Part A: Polym Chem 2006, 44, 2086-98.

515

chiral auxiliaries that bond via metal-ligand interactions.936 Templated polymerizations also

provide a route toward stereocontrol.937

Hydrogen bonding has only recently been employed as a means of influencing the

tacticity of radical polymerizations. Hirano et al reported slight changes in tacticity for

poly(N-isopropylacrylamide) that was polymerized in the presence of bulky diphosphates

which hydrogen bonded to the NH of the monomer.938 Okamoto’s939 and Kamigaito’s940

group has used the hydrogen bonding between bulky fluoroalcohols and esters to influence

the tacticity of radical polymerizations of vinyl ester monomers. Only slight changes in

tacticity (greater syndiotacticity) were observed. More recently, more Kamigaito’s group

utilized more sophisticated triple hydrogen bonding between diaminopyridine acrylamide

monomers and cyclic imide guests to influence tacticity of polymerizations.941 As expected,

the largest cyclic imide guest, naphthalimide, afforded the highest syndiotacticity (r = 71%,

versus 42% in the absence of naphthalimide).

936 Royles, J. L. R.; Sherrington, D. C. Transition metal complex-templated asymmetric free radical polymerisation. Chem Comm 1998, 421-2. 937 Serizawa, T.; Hamada, K.; Akashi, M. Polymerization within a molecular-scale stereoregular template. Nature 2004, 429, 52-5. 938 Hirano, T.; Kitajima, H.; Seno, M.; Sato, T. Hydrogen-bond-assisted stereocontrol in the radical polymerization of N-isopropylacrylamide with bidentate Lewis base. Polymer 2006, 47, 539-46. 939 Habaue, S.; Okamoto, Y. Stereocontrol in Radical Polymerization. Chem Record 2000, 46-52. 940 Koumura, K.; Satoh, K.; Kamigaito, M.; Okamoto, Y. Iodine Transfer Radical Polymerization of Vinyl Acetate in Fluoroalcohols for Simultaneous Control of Molecular Weight, Stereospecificity, and Regiospecificity. Macromolecules 2006, 39, 4054-61. 941 Wan, D.; Satoh, K.; Kamigaito, M. Triple Hydrogen Bonding for Stereospecific Radical Polymerization of a DAD Monomer and Simultaneous Control of Tacticity and Molecular Weight. Macromolecules 2006, 39, 6882-6.

516

The reversible attachment of guest molecules to polymers via nucleobase hydrogen

bonding has been investigated in both solution942 and the solid state.943,944 Rotello et al. have

used three-point hydrogen bonding between diacyldiaminopyridines and thymine to attach

guest molecules containing flavin945 or POSS to polystyrene.943 Hydrogen bonding guest

molecules can also increase the solubility of hydrogen bonding polymers via screening of

polymer-polymer self-association, thereby maintaining homogeneity during polymerization

reactions. 946 Multiple complementary association modes are possible for nucleobases,

including the classical Watson-Crick mode which is present in DNA as well as the less

commonly observed Hoogsteen association mode.947 Furthermore, nucleobases exhibit

several weak self-association modes (Ka<10 M-1),948 which compete with the complementary

association modes.

In this manuscript, we discuss the use of chiral auxiliaries containing hydrogen bonding

groups for the influence of tacticity of radical polymerizations (Figure 13.1). In particular,

942 Thibault, R. J.; Hotchkiss, P. J.; Gray, M.; Rotello, V. M. Thermally Reversible Formation of Microspheres through Non-Covalent Polymer Cross-Linking. J Am Chem Soc 2003, 125, 11249-52. 943 Carroll, J. B.; Waddon, A. J.; Nakade, H.; Rotello, V. M. “Plug and Play” Polymers. Thermal and X-ray Characterizations of Noncovalently Grafted Polyhedral Oligomeric Silsesquioxane (POSS)-Polystyrene Nanocomposites. Macromolecules 2003, 36, 6289-91. 944 Ilhan, F.; Gray, M.; Rotello, V. M. Reversible Side Chain Modification through Noncovalent Interactions. "Plug and Play" Polymers. Macromolecules 2001, 34, 2597-601. 945 Ilhan, F.; Galow, T. H.; Gray, M.; Clavier, G.; Rotello, V. M. Giant Vesicle Formation through Self-Assembly of Complementary Random Copolymers. J Am Chem Soc 2000, 122, 5895-6. 946 Stubbs, L. P.; Weck, M. Towards a Universal Polymer Backbone: Design and Synthesis of Polymeric Scaffolds Containing Terminal Hydrogen-Bonding Recognition Motifs at Each Repeating Unit. Chem Eur J 2003, 9, 992-9. 947 Ghosal, G.; Muniyappa, K. Hoogsteen base-pairing revisited: Resolving a role in normal biological processes and human diseases. Biochemical and Biophysical Research Communications 2006, 343, 1-7. 948 Kyogoku, Y.; Lord, R. C.; Rich, A. The Effect of Substituents on the Hydrogen Bonding of Adenine and Uracil Derivatives. Proc Natl Acad Sci USA 1967, 57, 250-7.

517

we examine complementary nucleobase hydrogen bonding between adenine and thymine

derivatives (Ka = 130 M-1 in chloroform)948 as a means to reversibly attach the chiral

auxiliary. Chiral hydrogen bonding molecular recognition has also played a large role in

supramolecular chemistry due to the ability to generate helical fibers and macroscopic

structures through “programming” that the chirality provides. 949 The use of chiral

nucleobases is advantageous due to the ready availability of chiral sugar-containing

nucleosides. The complementary nature of nucleobase hydrogen bonding is key to

minimizing competition from self-association of the hydrogen bonding monomers or chiral

auxiliary. Furthermore, nucleobase hydrogen bonding arrays are asymmetric, favoring

specific orientation of the chiral auxiliary.

949 Gulik-Krzywicki, T.; Fouquey, C.; Lehn, J. M. Electron microscopic study of supramolecular liquid crystalline polymers formed by molecular-recognition-directed self-assembly from complementary chiral components. Proc. Natl. Acad. Sci. USA 1993, 90, 163-7.

518

N O

N

O

H3C

R

O

O

O

O

NN

N

N NH

H

H

O

O

O

4

4

4

R =

Figure 13.1. Polymerization of a hydrogen bonded complex of a chiral auxiliary and a

complementary hydrogen bonding monomer.

HBHB

HB*

CB

A

*radical

polymerization

519

13.3 Experimental

13.3.1 Materials

Adenosine (99%), azobis(isobutyronitrile) (AIBN, 98%), hexanoic anhydride (97%),

pyridine (anhydrous, 99.8%), dimethyl sulfoxide (anhydrous, 99.9%),

N,N-dimethylformamide (DMF, anhydrous, 99.8%), thymine (99%), 1,2-dibromoethane

(99+%), hexamethyldisilazane (HMDS, 97%) sodium metal (99%) were obtained from

Aldrich and used as received. tert-Butanol (99.5%) was obtained from Aldrich and was

distilled from CaH2 prior to use. 1-vinylbenzylthymine950 and 1-methacryloxythymine951

were synthesized as previously described. V70 initiator was obtained from Wako Pure

Chemicals.

13.3.2 Synthesis of 2’,3’,5’-trihexyladenosine (AdHex)

Adenosine (0.504 g, 1.88 mmol), hexanoic anhydride (1.200 g, 5.61 mmol, 3 equiv),

pyridine (5 mL) and dimethyl sulfoxide (3 mL) were stirred at 25 oC for 16 h in a round

bottomed flask. The solvents were removed under reduced pressure (60 mtorr, 40 oC) and the

product was dissolved in hexane and washed with aqueous sodium bicarbonate. The solvent

was evaporated and the product was purified via chromatography on silica gel, eluting with

chloroform/methanol (95/5). AdHex was isolated as a colorless oil in 63% yield. 1H NMR

(DMSO-d6, δ, ppm): 0.83 (m, 9H), 1.23 (m, 12H), 1.47 (m, 4H), 1.56 (m, 2H), 2.18 (t, 1H),

950 Sedlak, M.; Simunek, P.; Antonietti, M. Synthesis and 15 NMR Characterization of 4-Vinylbenzyl Substituted Bases of Nucleic Acids. J Heterocyclic Chem 2003, 40, 671-75. 951 Akashi, M.; Tanaka, Y.; Iwasaki, H.; Miyauchi, N. Synthesis and Polymerization of New Vinyl Derivatives of Thymine. Angew. Makromol. Chem. 1987, 147, 207-13.

520

2.28 (m, 3H), 2.38 (m, 2H), 3.49 (dd, 1H), 4.34 (q, 1H), 4.40 (dd, 1H), 5.65 (t, 1H), 6.05 (t,

1H), 6.19 (d, 1H), 7.39 (br s, 2H), 8.15 (s, 1H), 8.34 (s, 1H). FAB MS: 562.327 m/z [M+H]+,

observed, 562.32 m/z [M+H]+ theoretical. [α]D = -36.8o (chloroform, 25 oC).

13.3.3 Synthesis of 1-(2-bromoethyl)thymine

Thymine (8.0 g, 63.5 mmol), HMDS (30 mL, 143 mmol, 2.25 equiv.) and DMF (5 mL)

were stirred at 130 oC for 18 h. A short-path distillation head and receiving flask were fitted

to the reaction flask and gentle (aspirator) vacuum was applied at 130 oC, resulting in

distillation of the residual HMDS and DMF. 1,2-dibromoethane (30 g, 162 mmol, 2.55 equiv)

and DMF (40 mL) were added and the mixture was stirred at 90 oC for 24 h. After cooling to

room temperature, DMF and unreacted 1,2-dibromoethane were removed under reduced

pressure (60 mtorr, 40 oC). The crude product was dissolved in THF (50 mL) and water (15

mL) was added to remove the silyl protecting groups, causing precipitation of thymine from

solution. The mixture was dried with rotary evaporation and methanol was added. The

unreacted thymine was filtered off with a sintered glass filter. The methanol solution was

evaporated, yielding 1-(2-bromoethyl)thymine as a white powder, 3.52 g, 24% yield. 1H

NMR (DMSO-d6, δ, ppm): 1.75 (s, 3H), 3.70 (t, 2H, J = 6.5 Hz), 4.02 (t, 2H, J = 6.5 Hz),

7.56 (s, 1H), 11.34 ppm (s, 1H).

13.3.4 Synthesis of 1-vinylthymine

Sodium (1.2 g, 52 mmol) was broken into small pieces and added to freshly distilled,

dry tert-butanol (200 mL). The mixture was stirred at 50 oC for 24 h with a bubbler to release

521

hydrogen gas until all of the sodium was consumed. 1-(2-bromoethyl)thymine (3.52 g, 15.2

mmol) was added into the solution and stirred at 60 oC for 48 h. After the reaction,

tert-butanol was removed under reduced pressure (60 mtorr, 40 oC) and water was added (100

mL) The solution was neutralized with HCl and the water was removed under reduced

pressure (60 mtorr, 40 oC). The crude product was chromatographed on silica, eluting with

chloroform/methanol (90/10). 1-vinylthymine was obtained as a cream-colored powder,

1.655 g, 72% yield. 1H NMR (CDCl3, δ, ppm): 1.99 (s, 3H), 4.91 (dd, 1H, J1 = 9.3 Hz, J2 =

2.2 Hz), 5.07 (dd, 1H, J1 =16.2 Hz, J2 = 2.2 Hz), 7.21 (dd, 1H, J1 = 15.8 Hz, J2 = 9.8 Hz),

7.34 (s, 1H), 9.01 (br s, 1H). FAB MS: m/z = 153.066 [M+H]+ (experimental), m/z = 153.066

[M+H]+ (theoretical).

13.3.5 Free radical polymerization of 1-vinylthymine

1-vinylthymine (152 mg, 1.00 mmol) and AIBN (2 mg, 0.012 mmol, 1.3 wt% relative to

monomer) were dissolved in DMSO-d6 (1.000 g) and degassed with repeated cycles of

vacuum (60 mtorr) followed by argon backfilling. The reaction was stirred at 65 oC for 48 h,

followed by precipitation in methanol. The fine powder product was collected via syringe

filter, dried under vacuum for 24 h, redissolved in DMSO-d6 and precipitated a second time

in methanol, followed by collection in a syringe filter. 1H NMR (DMSO-d6, δ, ppm): 0.7-2.5

(br m, 5H, backbone CH2 + thymine CH3), 3.5-5.3 (br m, 2H), 7-7.8 (br m, 0.2H), 10-10.8 (br

s, 1H), 11-11.5 (br m, 0.16H)

522

13.3.6 Polymerization of 1-vinylthymine in the Presence of a Chiral Auxiliary

AdHex (864 mg, 1.54 mmol) and 1-vinylthymine (233 mg, 1.53 mmol, 0.99 equiv) and

V70 initiator (60 mg, 0.169 mmol, 25 wt% relative to monomer) were dissolved in CDCl3

(5.64 g) and degassed by purging briefly with argon. The mixture was stirred for 72 h at 25

oC under argon during which time the reaction became cloudy. The polymer was isolated

via precipitation in methanol and filtered with a syringe filter.

13.3.7 Free radical polymerization of 1-vinylbenzylthymine

1-vinybenzylthymine (106 mg, 0.44 mmol) and AIBN initiator (7.1 mg, 0.043 mmol,

6.7 wt% relative to monomer) were dissolved in DMSO-d6 (1.14 g) and degassed by purging

briefly with argon. The mixture was stirred for 24 h at 70 oC under argon during which time

the reaction remained homogeneous. The polymer was isolated via precipitation in methanol.

1H NMR (DMSO-d6, δ, ppm): 1-2 (br, 6H, backbone + thymine CH3), 4.4-4.9 (br, 2H,

Ph-CH2-N), 6-7.5 (br, 5H, Ph + thymine C=CH), 11.3 (br s, 1H, thymine NH).

13.3.8 Polymerization of 1-vinylbenzylthymine in the Presence of a Chiral Auxiliary

AdHex (210 mg, 0.374 mmol) and 1-vinybenzylthymine (96 mg, 0.40 mmol, 1.06 equiv)

and V70 initiator (4.0 mg, 0.013 mmol, 4.2 wt% relative to monomer) were dissolved in

chloroform (1.05 g) and degassed by purging briefly with argon. The mixture was stirred for

24 h at 20 oC under argon during which time the reaction remained homogeneous. The

polymer was isolated via precipitation in methanol. Poly(1-vinylbenzylthymine), 26 mg, was

obtained as a white powder.

523


1H and 13C NMR spectroscopic data was collected in CDCl3 on a Varian 400 MHz

spectrometer at ambient temperature. FAB MS was conducted in positive ion mode on a

JEOL HX110 Dual Focusing Mass Spectrometer using xenon ion bombardment,

polyethylene glycol (PEG) standards and a 3-nitrobenzyl alcohol matrix. Optical rotation

measurements were conducted on a Perkin Elmer 241 polarimeter using the sodium D line.


A chloroform soluble, chiral auxiliary containing adenine (AdHex) was synthesized in a

single step from commercially available adenosine (Figure 13.2). The solubility in

chloroform was a critical feature for the chiral auxiliary since hydrogen bonding interactions

are screened by more polar solvents which typically dissolve nucleobase functionalized

compounds such as DMSO, water or DMF. The acylation of the adenine hydroxyl groups

occurred selectively over reaction with the adenine NH2 as indicated by the presence of the

NH2 protons in the 1H NMR spectrum (7.39 ppm, DMSO-d6). The reaction was analogous to

a literature procedure for acetylation of adenosine.952 Acetylated adenosine was also

synthesized according to the literature, however it proved insoluble in chloroform. The

optical rotation of AdHex, ([α]D = -36.8o chloroform, 25 oC) was similar to that of acetylated

adenosine ([α]D = -37.6o, DMSO-d6, 25 oC) suggesting retention of chirality. The adenosine

precursor possesses an optical rotation of -60o (H2O, 24 oC) according to the literature.953

952 Bajji, A. C.; Davis, D. R. Synthesis of the tRNALys,3 Anticodon Stem-Loop Domain Containing the Hypermodified ms2t6A Nucleoside. J Org Chem 2002, 67, 5352-8. 953 Stecher, P. G.; Finkel, M. J.; Siegmund, O. H.; Szafranski, B. M., Merck Index. 7 ed.; Merck and Co: Rahway, NJ, 1960.

524

OH

OH

OH

O

N

N

NH2

N

N

O

O

O

O

N

N

NH2

N

NO

O

O

hexanoic anhydride

pyridine, 25 oC, 16 h

Figure 13.2. Synthesis of a chloroform soluble chiral auxiliary (AdHex) for polymerization of

complementary thymine or uracil-containing monomers.

AdHex

525

The chiral auxiliary was introduced into radical polymerizations of

1-vinylbenzylthymine, a monomer which possesses a phenyl group between the

polymerizable vinyl group and the thymine nucleobase (Figure 13.3). The polymerization

of 1-vinylbenzylthymine was first conducted in a polar solvent, DMSO-d6, in the absence of

the chiral auxiliary. In order to carry out the polymerization with the chiral auxiliary,

conditions were chosen that were expected to maximize the level of association. Thus, the

reactions were run in chloroform, at 20 oC, using a low-temperature initiator, V-70 and one

equivalent of the AdHex. The polymerizations in both cases remained homogeneous and

the resulting poly(1-vinylbenzylthymine)s were precipitated in methanol as a white powder.

The 1H NMR spectra of the polymers from these two separate routes are shown in Figure

13.4 (1-1.8 ppm, DMSO-d6). Changes in tacticity of vinyl polymers, such as PMMA954 are

often observed in 1H NMR through the backbone or side-chain resonances. This typically

provides information to the diad level (m = meso, r = racemic) or triad level (mm (isotactic),

rr (syndiotactic), rm (heterotactic)). However, for polystyrene, tacticity is more difficult to

obtain from NMR and detailed information is only obtained through quantitative 13C

NMR.955 Unfortunately, for these polymers, the quantity of material obtained from the

polymerizations was not sufficient to obtain 13C NMR spectra. Harwood and coworkers were

able to assign proton NMR resonances to triad structures for substituted polystyrenes such as

poly(4-acetylstyrene). 956 The similarity of the proton NMR spectra for

954 Carriere, P.; Grohens, Y.; Spevacek, J.; Schultz, J. Stereospecificity in the Adsorption of Tactic PMMA on Silica. Langmuir 2000, 16, 5051-3. 955 Pasch, H.; Hiller, W.; Haner, R. Investigation of the tacticity of oligostyrenes by on-line HPCL/1H NMR. Polymer 1998, 39, 1515-23. 956 Trumbo, D. L.; Chen, T.-K.; Harwood, H. J. Observation of Triad Sequences in a Polystyrene Derivative. Macromolecules 1981, 14, 1138-9.

526

poly(1-vinylbenzylthymine) was interpreted to indicate similar tacticity. This lack of a clear

difference suggested that the radical propagating chain end was too distant from the chiral

center to be influenced.

527

NO

HN

O

AdHexCHCl320 oC, 16 h

V70

NO

HN

O

DMSO-d670 oC, 16 h

AIBN

N

ONH

O

N

ONH

O

N NNC

O

CN

O

V70

Figure 13.3. Polymerization of 1-vinylbenzylthymine with and without added chiral auxiliary

AdHex.

528

Figure 13.4. 1H NMR spectra of poly(1-vinylbenzylthymine) polymerized in the absence (a)

or presence (b) of chiral auxiliary AdHex. (DMSO-d6). Sharp peaks represent impurities

(residual monomer, solvents).

a)

b)

529

In order to bring the chiral center closer to the propagating radical chain end, hydrogen

bonding monomers possessing shorter distances between the nucleobase and the vinyl group

were pursued. Thus, 1-methacryloxythymine was synthesized according to a literature

procedure.957 The methacrylate monomer also benefits from the ability to determine tacticity

through 1H NMR spectroscopy from the α-methyl resonances. However, this monomer was

found not to homopolymerize even under conventional conditions (3 wt% BPO, DMSO, 80

oC, 16 h). The literature also confirmed difficulty in the polymerization of this monomer,

reporting polymerization yields of only 7%.957 Alternately, 1-acryloxythymine was reported

to provide higher polymerization yields (86%),957 but the synthesis of this monomer was

unsuccessful despite repeated attempts. Michael addition side reactions of the acrylate group

with the thymine NH were detected in 1H NMR spectra and the literature reported low yields

of the monomer (36%).957

Abandoning an acrylic nucleobase-containing monomer, attention was turned to a

monomer with even shorter distance between the propagating center and the nucleobase.

1-vinylthymine was synthesized in four steps from thymine (Figure 13.5). This monomer was

previously homopolymerized by Kondo et al. via free radical methods (AIBN, DMSO, 95 oC)

with reported yields of 30%.958 The analogous 1-vinyluracil monomer was reported to yield

nearly quantitative polymerization conversion, however, this was complicated by significant

957 Akashi, M.; Tanaka, Y.; Iwasaki, H.; Miyauchi, N. Synthesis and Polymerization of New Vinyl Derivatives of Thymine. Angew. Makromol. Chem. 1987, 147, 207-13. 958 Kondo, K.; Iwasaki, H.; Nakatani, K.; Ueda, N.; Takemoto, K.; Imoto, M. Vinyl Compounds of Nucleic Acid Bases. 3. Polymerization and Copolymerization of N-Vinyl and B-Methacryloyloxyethyl Compounds of Nucleic Acid Bases and their Polymer-Polymer Interactions. Die Makromolecular Chemie 1969, 125, 42-7.

530

amounts of “cyclopolymerization” involving reaction of the internal double bond present in

uracil as reported by Kaye.959

959 Kaye, H. Cyclopolymerization of N-Vinyluracil. Macromolecules 1971, 4, 147-52.

531

NH

O

HN

O

NO

HN

O

Br

NaOtBu

t-BuOH60 oC48 h

NO

HN

O

NH

TMSO

HN

OTMS

Br

Br

DMF90 oC24 h

HMDS

DMF130 oC18 h

2.5

Figure 13.5. Synthesis of 1-vinylthymine.

532

1-vinylthymine was polymerized using conventional radical polymerization conditions

(AIBN, DMSO-d6, 65 oC). 1-vinylthymine was also polymerized in the presence of AdHex in

CDCl3 at 25 oC, with the low-temperature initiator V-70. This resulted in very low conversion,

and the product was isolated via syringe filtering. As for the case of 1-vinylbenzylthymine,

the 1H NMR spectra were very similar (Figure 13.6) suggesting a lack of influence on

tacticity. However, the most closely related common polymer, poly(N-vinyl pyrrolidone),

requires 13C NMR spectroscopy for tacticity determination.960 The determination of the

effect of the chiral auxiliary was complicated by the necessary low scale of the

polymerization reactions and the low conversions obtained. Typically for quantitative 13C

NMR, at least 300 mg of polymer is required.

960 Wan, D.; Satoh, K.; Kamigaito, M., Okamoto, Y. Xanthate-Mediated Radical Polymerization of N-Vinylpyrrolidone in Fluoroalcohols for Simultaneous Control of Molecular Weight and Tacticity. Macromolecules 2005, 38, 10397-405.

533

Figure 13.6. 1H NMR spectrum of poly(1-vinylthymine) polymerized in the presence (a) and

absence (b) of AdHex.

a)

b)

534

13.5 Conclusions

Hydrogen bonding monomers containing nucleobases (1-vinylthymine and

1-vinylbenzylthymine) were synthesized and polymerized in the presence or absence of

complementary (adenine) hydrogen bonding derivatives possessing chirality. The influence of

the chiral auxiliary guests on the tacticity of the polymers was analyzed by 1H NMR

spectroscopy. Polymerization of thymine-containing monomers in the presence of an

acylated, chiral adenosine derivative yielded polymers with similar 1H NMR spectrum to

those obtained for radical polymerizations conducted in the absence of the chiral auxiliary.

13.6 Future Work

The next steps in this project involve finding reaction conditions or hydrogen bonding

monomers which lead to high yields for polymerization. This is necessary in order to obtain

necessary sample quantities for 13C NMR analysis.





535

Chapter 14. Future Directions- Rheological Studies of Hydrogen

Bonding Copolymers with Reversible Attachment of Ionic

Functionality

14.1 Abstract

Random copolymers of a phosphonium styrene monomer and n-butyl acrylate were

synthesized in order to compare the covalent attachment of phosphonium ions to hydrogen

bonding attachment. Hydrogen bonding attachment of ionic groups was achieved through

blending of an adenine containing copolymer with a complementary uracil phosphonium salt.

Partial miscibility of the uracil phosphonium salt with the 2.0 mol% adenine-functional

copolymer was observed. Rheological studies indicated strong attachment of the uracil

phosphonium salt, with rheological behavior of the blend mirroring that of the covalent

copolymer across the range of temperatures studied. Covalent phosphonium copolymers

with higher incorporation of the phosphonium salt monomer (30 mol%) resulted in increased

Tg, a broad maximum in the small-angle X-ray scattering curve and multiple transitions

above Tg in dynamic mechanical analysis, suggesting ionic aggregation.

536

14.2 Introduction

Ionic interactions have been studied in polymer systems for several decades.961962

- 963

These strong, electrostatic interactions possess enthalpies approximately one order of

magnitude stronger than hydrogen bonding interactions (~200 kJ/mol).964 Furthermore,

these coulombic interactions are non-specific and occur over longer distances than hydrogen

bonding interactions. Ion-containing random copolymers which possess less than 15 mol% of

ionic groups are termed ionomers. Typically, these ionomers consist of a relatively low

dielectric constant, non-ionic, comonomer, which is designed to maximize ionic association.

These ionomers possess ionic aggregates due to the association of the ionic species. Recently,

Winey et al. thoroughly characterized these ionic aggregates via SAXS and STEM.965 The

presence of the ionic aggregates in polymers results in improved high temperature

mechanical properties and better toughness and abrasion resistance, as well as improved

chemical resistance due to the insolubility of the ionic groups in hydrocarbon solvents.

Decreases in compression set,966 tensile set, hysteresis and creep were also observed.

Materials such as DuPont’s Surlyn® (an ionomer of an ethylene methacrylic acid copolymer)

961 Eisenberg, A.; Hird, B.; Moore, R. B. A New Multiplet-Cluster Model for the Morphology of Random Ionomers. Macromolecules 1990, 23, 4098-107. 962 Eisenberg, A. Clustering of Ions in Organic Polymers. A Theoretical Approach. Macromolecules 1970, 3, 147-54. 963 Duvdevani, I.; Lundberg, R. D.; Wood-Cordova, C.; Wilkes, G. L., Coulombic Interactions in Macromolecular Systems. In ACS Symposium Series, Eisenberg, A.; Bailey, F. E., Eds. American Chemical Society: Washington DC, 1986; Vol. 302, pp 185-99. 964 Hird, B.; Eisenberg, A. Sizes and Stabilities of Multiplets and Clusters in Carboxylated and Sulfonated Styrene Ionomers. Macromolecules 1992, 25, 6466-74. 965 Benetatos, N. M.; Heiney, P. A.; Winey, K. I. Reconciling STEM and X-ray Scattering Data from a Poly(styrene-ran-methacrylic acid) Ionomer: Ionic Aggregate Size. Macromolecules 2006, 39, 5174-6. 966 Balas, J. G.; Gergen, W. P.; Willis, C. L.; Pottick, L. A.; Gelles, R.; Weiss, R. A. Sulfonated block copolymers. US Patent 5239010, 1993.

537

are typically used for golf ball covers, due to the outstanding mechanical properties conferred

from the ionic association. Exxon studied sulfonated EPDM (ethylene propylene diene

rubber) as a tough, chemical resistant elastomer.967 A further advantage of ionic polymers is

the ability to conduct ions, which enables applications in ion-conducting membranes,968 fuel

cells, 969 electromechanical devices, 970 water purification membranes 971 and breathable

textiles for protection against chemical warfare agents.972

While the properties of ionomers are impressive, they come at the cost of processability.

Due to the high temperature stability of ionic aggregates (which can persist to temperatures of

300 oC),973 these materials are often difficult to process via extrusion or melt compounding

techniques due to their high melt viscosity.974 Earlier efforts to improve the processability of

sulfonated EPDM centered on the addition of zinc stearate, which possesses long aliphatic

967 Agarwal, P. K.; Lundberg, R. D. Viscoelastic behavior of concentrated oil solutions of sulfo polymers. 2. EPDM and zinc sulfo-EPDMs. Macromolecules 1984, 17, 1918. 968 Elabd, Y. A.; Walker, C. W.; Beyer, F. L. Triblock copolymer ionomer membranes: Part II. Structure characterization and its effects on transport properties and direct methanol fuel cell performance. J. Membr. Sci. 2004, 231, 181-8. 969 Roy, A.; Hickner, M. A.; Yu, X.; Li, Y.; Glass, T.; McGrath, J. E. Influence of Chemical Composition and Sequence Length on the Transport Properties of Proton Exchange Membranes. J Polym Sci, Part B: Polym Phys 2006, 44, 2226-39. 970 Akle, B.; Leo, D. J.; Hickner, M. A.; McGrath, J. E. Correlation of capacitance and actuation in ionomeric polymer transducers. J Mater Sci 2005, 40, 3715-24. 971 Takizawa, M.; Sugito, Y.; Oguma, N.; Nakamura, M.; Horiguchi, S.; Fukutomi, T. Charge-Mosaic Membrane Prepared from Microspheres. J Polym Sci, Part A: Polym Chem 2003, 41, 1251-61. 972 Rivin, D.; Meermeier, G.; Schneider, N. S.; Vishnyakov, A.; Neimark, A. V. Simultaneous Transport of Water and Organic Molecules through Polyelectrolyte Membranes. J. Phys. Chem. B 2004, 108, 8900-8909. 973 Lu, X.; Steckle, W. P.; Hsiao, B.; Weiss, R. A. Thermally Induced Microstructure Transitions in a Block Copolymer Ionomer. Macromolecules 1995, 28, 2831-9. 974 Weiss, R. A.; Fitzgerald, J. J.; Kim, D. Viscoelastic Behavior of Plasticized Sulfonated Polystyrene Ionomers. Macromolecules 1991, 24, 1064-70.

538

chains as well a carboxylate ion, which “plasticized” the ionic aggregates when heated above

its melting point (128 oC).963

The use of phosphonium cations to introduce ionic interactions has spurred recent

research into phosphonium ionomers. 975 , 976 Phosphonium salts benefit from better

compatibility with organic media compared to sulfonate and carboxylate salts. Random

phosphonium containing ionomers possess thermoplastic elastomeric properties977,978 due to

the presence of ionic aggregates,979 as in sulfonated and other ionomers. Furthermore, the

ability of phosphonium salts to aggregate is tuned via the length of the substituents attached

to phosphorus. Also, phosphonium salts possess greater thermal stability than the

corresponding ammonium salts,975 which decompose via Hofmann elimination reactions at

200 oC.980 Phosphonium salts and ionomers often possess antibacterial981 and phase transfer

catalytic activity. Applications for phosphonium ionomers in the areas of ionically conductive

975 Unal, S.; McKee, M. G.; Massa, D. J.; Long, T. E. Synthesis and characterization of phosphonium-based telechelic polyester ionomers. . Polym Prep 2005, 46, 1028-9. 976 Ghassemi, H.; Riley, D. J.; Curtis, M.; Bonaplata, E.; McGrath, J. E. Main-Chain Poly(arylene ether) Phosphonium Ionomers. Appl Organometal Chem 1998, 12, 781-5. 977 Arjunan, P.; Wang, H.-C.; Olkusz, J. A., Functional Polymers. American Chemical Society: Washington DC, 1998; Vol. 704, p 199-216. 978 Lindsell, W. E.; Radha, K.; Soutar, I.; Stewart, M. J. The preparation and characterization of phosphorus-terminated poly-l,3-butadiene: new telechelic ionomers. Polymer 1990, 31, 1374-8. 979 Parent, J. S.; Penciu, A.; Guillen-Castellanos, A.; Liskova, A.; Whitney, R. A. Synthesis and Characterization of Isobutylene-Based Ammonium and Phosphonium Bromide Ionomers. Macromolecules 2004, 37, 7477-83. 980 Burch, R. R.; Manring, L. E. N-Alkylation and Hofmann Elimination from Thermal Decomposition of R4N+ Salts of Aromatic Polyamide Polyanions: Synthesis and Stereochemistry of N-Alkylated Aromatic Polyamides. Macromolecules 1991, 24, 1731-5. 981 Kanazawa, A.; Ikeda, T.; Endo, T. Polymeric phosphonium salts as a novel class of cationic biocides. IX. Effect of side-chain length between main chain and active group of antibacterial activity. J Polym Sci, Part A: Polym Chem 1994, 32, 1997-2001.

539

membranes, polymer battery components and water dispersable fiber sizings were

envisioned.976

We propose the use of hydrogen bonding to allow reversible attachment of the ionic

species. We propose that the thermoreversible properties conferred by hydrogen bonds will

enable improved processability of ion-containing polymers. The reversible attachment of

guest molecules to polymers via nucleobase hydrogen bonding has been investigated in both

solution982 and the solid state.983,984 Rotello et al. have used three-point hydrogen bonding

between diacyldiaminopyridines and thymine to attach guest molecules containing flavin985

or POSS to polystyrene.983 Hydrogen bonding guest molecules can also increase the

solubility of hydrogen bonding polymers via screening of polymer-polymer self-association,

thereby maintaining homogeneity during polymerization reactions. 986 Multiple

complementary association modes are possible for nucleobases, including the classical

Watson-Crick mode which is present in DNA as well as the less commonly observed

Hoogsteen association mode. 987 Furthermore, nucleobases exhibit several weak

982 Thibault, R. J.; Hotchkiss, P. J.; Gray, M.; Rotello, V. M. Thermally Reversible Formation of Microspheres through Non-Covalent Polymer Cross-Linking. J Am Chem Soc 2003, 125, 11249-52. 983 Carroll, J. B.; Waddon, A. J.; Nakade, H.; Rotello, V. M. “Plug and Play” Polymers. Thermal and X-ray Characterizations of Noncovalently Grafted Polyhedral Oligomeric Silsesquioxane (POSS)-Polystyrene Nanocomposites. Macromolecules 2003, 36, 6289-91. 984 Ilhan, F.; Gray, M.; Rotello, V. M. Reversible Side Chain Modification through Noncovalent Interactions. "Plug and Play" Polymers. Macromolecules 2001, 34, 2597-601. 985 Ilhan, F.; Galow, T. H.; Gray, M.; Clavier, G.; Rotello, V. M. Giant Vesicle Formation through Self-Assembly of Complementary Random Copolymers. J Am Chem Soc 2000, 122, 5895-6. 986 Stubbs, L. P.; Weck, M. Towards a Universal Polymer Backbone: Design and Synthesis of Polymeric Scaffolds Containing Terminal Hydrogen-Bonding Recognition Motifs at Each Repeating Unit. Chem Eur J 2003, 9, 992-9. 987 Ghosal, G.; Muniyappa, K. Hoogsteen base-pairing revisited: Resolving a role in normal biological processes and human diseases. Biochemical Biophysical Research Communications 2006, 343, 1-7.

540

self-association modes (Ka<10 M-1),988 which compete with the complementary association

modes. We recently discussed the hydrogen bonding attachment of phosphonium ionic

groups to nucleobase containing block copolymers.

In this chapter, we compare the non-covalent attachment of phosphonium salts to the

covalent attachment (Figure 14.1). Assuming that ionic interactions are present in

phosphonium containing polymers, one would expect effects on rheology due to ionic

attractions and ionic aggregates. The use of hydrogen bonding to reversibly attach the ionic

groups to the backbone should allow dissociation of these ionic groups and produce a lower

viscosity.

988 Kyogoku, Y.; Lord, R. C.; Rich, A. The Effect of Substituents on the Hydrogen Bonding of Adenine and Uracil Derivatives. Proc Natl Acad Sci USA 1967, 57, 250-7.

541

Figure 14.1. Pictorial representation of ionic groups hydrogen bonded to a polymer chain (a)

as well as a covalent analog (b).

N

N

NH

NN

HN

ON

O

H H

P+

Cl-R

RR

P

R

RR Cl

a) b)

542

14.3 Experimental

14.3.1 Materials

n-Butyl acrylate (Aldrich, 99%) was deinhibited via passage through an alumina column.

Azobis(isobutyronitrile) (AIBN, 98%), 2,6-di-tert-butyl-4-methylphenol (BHT, 99%),

trioctylphosphine (90%, tech. grade), vinylbenzyl chloride (mixture of meta and para isomers,

97%) and 6-chloromethyluracil (98%) were obtained from Aldrich and used as received.

9-vinylbenzyladenine was synthesized as described elsewhere.989

14.3.2 Phosphonium Styrene Monomer Synthesis

Vinylbenzyl chloride (2.02 g, 13.2 mmol), BHT (10 mg) and hexanes (25 mL) were

combined in a 100 mL round-bottomed flask containing a magnetic stirbar. The flask was

sealed with a rubber septum and the solution was purged with argon using a long needle

inserted into the solution and a vent needle. Trioctylphosphine (6.56 mL, 13.2 mmol at 90%

purity) was injected via syringe and the reaction was heated to 60 oC and stirred for 24 h. The

reaction was cooled to room temperature, upon which the product crystallized from the

reaction medium. The product was separated by filtration and washed with cold hexanes. The

product was recrystallized from hexanes. Yield 4.78 g, 69%. FAB MS: m/z = 487.442

[M-Cl]+ (experimental), m/z = 487.443 [M-Cl]+ (theoretical). 1H NMR (CDCl3, δ, ppm): 0.87

(t, 9H, CH3), 1.23 (m, 24H, octyl CH2), 1.42 (m, 12H, octyl CH2), 2.41 (br, 6H, P-CH2), 4.31

(d, 2H, J = 13.9 Hz, Ph-CH2-P), 5.29 (dd, 1H, J1 = 11 Hz, J2 = 4.3 Hz, trans Ph-CH=CH2),

989 Srivatsan, S. G.; Parvez, M.; Verma, S. Modeling of Prebiotic Catalysis with Adenylated Polymeric Templates: Crystal Structure Studies and Kinetic Characterization of Template-Assisted Phosphate Ester Hydrolysis. Chem. Eur. J. 2002, 8, 5184-91.

543

5.77 (dd, 1H, J1 =17.3 Hz, J2 =11.1 Hz, cis Ph-CH=CH2), 6.68 (dd, 1H, J1 = 17.5 Hz, J2 =

10.8 Hz, Hz Ph-CH=CH2), 7.3-7.45 (m, 4H, Ph). 31P NMR (CDCl3, δ, ppm): 31.46, 31.57.

14.3.3 Uracil Phosphonium Salt

6-chloromethyluracil (1.001 g, 6.232 mmol) and trioctylphosphine (3.25 mL, 2.70 g,

7.29 mmol) were charged to a 100 mL round-bottomed flask containing a magnetic stirbar.

Ethanol (40 mL) was added and a condenser was fitted to the flask. The reaction was heated

to reflux using an external oil bath for 24 h. Excess solvent was removed using rotary

evaporation. The resulting waxy solid was washed with diethyl ether and was dried overnight

at room temperature under high vacuum. UP+ was obtained as a light brown solid (m.p.

179-181 °C) in 88% yield. 1H NMR (DMSO-d6, δ, ppm): 0.86 (t, 9H, J = 6.8 Hz), 1.26 (m,

24H), 1.37 (m, 6H), 1.49 (m, 6H), 2.37 (m, 6H), 3.77 (d, 2H, J = 15 Hz), 5.55 (m, 1H), 11.15

(s, 1H), 11.47 (s, 1H). 13C NMR (DMSO-d6, δ, ppm) : 13.96, 17.61, 18.06, 20.52, 22.08, 28.27,

28.8, 30.06, 31.22, 102.08, 145.18, 150.95, 163.37. 31P NMR (DMSO-d6, δ, ppm) : 33.68 ppm.

FAB MS: m/z = 495.4056 [M-Cl]+ (experimental), m/z = 495.41 (theoretical).

14.3.4 Adenine Containing Copolymer

9-vinylbenzyladenine (0.392 g, 1.56 mmol), n-butyl acrylate (10 mL, 70.2 mmol),

AIBN (30 mg, 0.32 wt% relative to monomer) and THF (33 mL) were combined in a 100 mL

round-bottomed flask containing a magnetic stirbar. The flask was sealed with a rubber

septum and the solution was purged with argon using a long needle inserted into the solution

and a vent needle. The polymerization was conducted at 60 oC for 48 h. The product was

544

isolated as a viscous liquid polymer by precipitation in methanol/water (90/10 v/v) and dried

at 50 oC under vacuum for 18 h. Yield 7.00 g (75%). 1H NMR (CDCl3) revealed a

9-vinylbenzyladenine content of 2.0 mol% as determined by comparing the integration of the

benzyl CH2 protons (5.25 ppm) and the n-butyl acrylate ester CH2 protons (3.7-4.0 ppm).

SEC in THF using a light scattering detector produced molecular weights of Mn = 17700, Mw

= 32600, Mw/Mn = 1.84.

14.3.5 Phosphonium Salt Containing Copolymer

Phosphonium styrene monomer (1.42 g, 2.71 mmol), n-butyl acrylate (10 mL, 70.2

mmol), AIBN (25 mg, 0.24 wt% relative to monomer), THF (20 mL) and methanol (14 mL)

were combined in a 100 mL round-bottomed flask containing a magnetic stirbar. The flask

was sealed with a rubber septum and the solution was purged with argon using a long needle

inserted into the solution and a vent needle. The polymerization was conducted at 60 oC for

48 h. The product was isolated by precipitation in methanol/water (90/10 v/v) and dried at 50

oC under vacuum for 18 h. Yield 4.16 g, 40%. 1H NMR (CD2Cl2) revealed a phosphonium

styrene content of 2.08 mol% as determined by comparing the integration of the phenyl

protons (6.9-7.5 ppm) and the n-butyl acrylate ester CH2 protons (3.7-4.0 ppm). SEC in THF

using a light scattering detector produced a bimodal molecular weight distribution with Mn1 =

21300, Mw1 = 31000, Mw1/Mn1 = 1.46 (98 wt% of sample), Mn2 = 151900, Mw2 = 780000,

Mw2/Mn2 = 5.12 (1.9 wt% of sample).

A copolymer with a higher content of phosphonium styrene monomer was also

synthesized. Phosphonium styrene monomer (2.85 g, 5.44 mmol), n-butyl acrylate (3.7 mL,

545

26.6 mmol), AIBN (15 mg, 0.24 wt% relative to monomer) and methanol (30 mL) were

combined in a 100 mL round-bottomed flask containing a magnetic stirbar. The flask was

sealed with a rubber septum and the solution was purged with argon using a long needle

inserted into the solution and a vent needle. The polymerization was conducted at 60 oC for

48 h. The product was isolated by precipitation in hexanes and dried at 50 oC under vacuum

for 18 h. 1H NMR (CD2Cl2) revealed a phosphonium styrene content of 30.0 mol% as

determined by comparing the integration of the phenyl protons (6.9-7.5 ppm) and the n-butyl

acrylate ester CH2 protons (3.7-4.0 ppm). SEC in THF was attempted by Eastman and found

to be unsuccessful due to adsorption to the column.

14.3.6 Blends of an Adenine Containing Copolymer with a Uracil Phosphonium Salt

Adenine containing copolymer (3.00g, 2.0 mol%, 3.8 wt% comonomer, 0.454 mmol

adenine, Mw = 32600) was weighed into a vial. Uracil phosphonium salt (244 mg, 0.460

mmol) was added to the vial. Tetrahydrofuran (5 mL) followed by chloroform (5 mL) were

added and the mixture dissolved completely. The solvent was removed via rotary

evaporation and the sample was dried under vacuum at 50 oC for 18 h.


1H and 13C NMR spectroscopic data was collected in CDCl3 on a Varian 400 MHz

spectrometer at ambient temperature. FAB MS was conducted in positive ion mode on a

JEOL HX110 Dual Focusing Mass Spectrometer using xenon ion bombardment,

polyethylene glycol (PEG) standards and a 3-nitrobenzyl alcohol matrix. DSC was conducted

546

on a TA Instruments Q1000 DSC at a heating rate of 20 oC/min under nitrogen. Rheological

studies were conducted on a TA Instruments G2 rheometer in parallel plat configuration at a

frequency of 1 Hz using 5% strain. The samples were determined to be in the linear

viscoelastic regime at this strain value.


A copolymer of 9-vinylbenzyladenine and n-butyl acrylate was synthesized using

conventional free radical techniques (Figure 14.2). 9-vinylbenzyladenine is a styrenic

nucleobase-containing monomer which was synthesized according to literature procedures.

The n-butyl acrylate comonomer was chosen for the low glass transition temperature of

poly(n-butyl acrylate) (-40 oC), which would cause the copolymers to exist as liquids at room

temperature, and would facilitate rheological experiments of studying hydrogen bonding

interactions which usually dissociate at temperatures below 100 oC. The polar solvent THF

was utilized due to the limited solubility of the adenine containing monomer in less polar

solvents (ethyl acetate). The copolymer contained a low level of adenine comonomer (2.0

mol%) and possessed a low molecular weight (Mw ~ 32600).

547

OO

Bu

N

N

N

N

N H

H

n-butyl acrylateAIBN

THF60 oC48 h

N

N

NH2

N

N

Figure 14.2. Synthesis of an adenine-containing random copolymer.

548

A phosphonium salt-containing copolymer was synthesized using a phosphonium

containing styrenic monomer (Figure 14.3). Initially, polymerizations were conducted in THF,

however, it was found that this resulted in very low incorporation of the phosphonium

monomer into the polymer. Addition of methanol to the polymerization (40 vol%) resulted in

improved incorporation (to 55% of targeted levels) and the polymerizations remained

homogeneous. The mixture with THF was chosen to maintain the solubility of the

poly(n-butyl acrylate) sequences, which are insoluble in methanol. The copolymers with the

phosphonium monomer were also viscous liquids at room temperature and had similar

comonomer levels compared to the adenine containing copolymers (2.08 mol%).

549

OO

Bu

P

oct

oct octCl

n-butyl acrylate0.3 wt% AIBN

THF/MeOH60 oC48 h

P octoct

octCl

Figure 14.3. Synthesis of a phosphonium styrene containing random copolymer.

550

A copolymer with a higher content of phosphonium comonomer was synthesized using

pure methanol solvent. This resulted in nearly quantitative incorporation of the phosphonium

salt monomer (copolymer contained 30 mol%). SEC was challenging for the phosphonium

containing copolymers. SEC in THF for the 2 mol% sample produced bimodal molecular

weight distributions according to both light scattering (MALLS) and RI detectors. The main

portion of the sample (98 wt%) possessed a molecular weight of Mw = 31000 (Mw/Mn = 1.46).

A small portion of the sample (2 wt%) existed as a broad, high molecular weight peak Mw =

780000 (Mw/Mn = 5.12). No reason could be found for the presence of such high molecular

weight material in the sample, and repeated synthesis produced the same result. SEC was

attempted at Eastman on the 30 mol% copolymer, however, this resulted in adsorption to the

columns and no signal was obtained. The adsorption of the 30 mol% copolymer suggested

that similar effects could be responsible for the anomalous SEC of the 2 mol% samples.

DSC analysis of the 30 mol% phosphonium styrene copolymer (Figure 14.4) indicated a

broad glass transition temperature centered at 10.7 oC over a range of about 35 oC. This Tg

was significantly higher than that of n-butyl acrylate homopolymer (-40 oC), likely due to a

copolymer effect, since the Tg of a pure phosphonium-containing styrenic polymer is

expected to be above that of poly(n-butyl acrylate).

551

-1.0

-0.5

0.0

Hea

t Flo

w (W

/g)

-70 -20 30 80Temperature ( C)Exo Up Universal V3.9A TA Instruments

Figure 14.4. DSC analysis of phosphonium styrene copolymer (30 mol%).

Tg = 10.7 oC

o

552

Small-angle x-ray scattering was conducted on the 30 mol% copolymer, in order to look

for ionic aggregates (Figure 14.5). X-ray scattering revealed a broad scattering maximum at

q = 3.75 nm-1. The scattering maximum was weak, but it was located close to those

observed for other ionomers. Winey et al. observed an ionomer peak at q = 3.7 nm-1 for

poly(styrene-co-methacrylic acid) neutralized with copper (II) salts.990 The Yarusso-

Cooper model, which was developed to model scattering from ionomeric aggregates,991 was

utilized to fit the scattering maxima. The fitting parameters for the Yarusso-Cooper model,

the aggregate radius (R1) and the radius of closest approach between aggregates (Rca)

matched closely with those observed by Winey et al. for the copper-neutralized

styrene-methacrylic acid ionomers, whereas the volume of polymer per aggregate (Vp) was

significantly lower (Table 14.1). The difference in the Vp values observed was attributed to

the level of ionic groups present in the current copolymer (30 mol%) compared with the

polymer studied by Winey (6.2 mol%). If the higher mole fraction in the current study

resulted in the formation of more aggregates, then one would expect the volume of polymer

per aggregate to decrease.

990 Benetatos, N. M.; Heiney, P. A.; Winey, K. I. Reconciling STEM and X-ray Scattering Data from a Poly(styrene-ran-methacrylic acid) Ionomer: Ionic Aggregate Size. Macromolecules 2006, 39, 5174-6. 991 Yarusso, D.J.; Cooper, S.L. Microstructure of Ionomers: Interpretation of Small-Angle X-ray Scattering Data. Macromolecules 1983, 16, 1871-80.

553

0.01

0.1

1

10

0 0.1 0.2 0.3 0.4 0.5

q (A-1)

Inte

nsity

Raw DataYarusso-Cooper Fit

Figure 14.5. Small-angle X-ray scattering of 30 mol% phosphonium copolymer.

554

Table 14.1. Yarusso-Cooper fitting of scattering for 30 mol% phosphonium copolymer.

Sample R1 (nm) Rca (nm) Vp (nm3)

Phosphonium

Copolymers

0.56 0.70 2.3

Styrene-methacrylic

acid copolymers

(Winey et al.)992

0.50 0.71 4.2

992 Benetatos, N. M.; Heiney, P. A.; Winey, K. I. Reconciling STEM and X-ray Scattering Data from a Poly(styrene-ran-methacrylic acid) Ionomer: Ionic Aggregate Size. Macromolecules 2006, 39, 5174-6.

555

Dynamic mechanical analysis was utilized to study the 30 mol% phosphonium

copolymer (Figure 14.6). The polymer, which was a tough, glassy solid, was melt pressed to

obtain film samples. DMA revealed multiple transitions including a Tg at 20 oC (E”

maximum) and additional transitions near 38 and 56 oC. The primary maximum in the tan

delta curve occurred at 45 oC. The additional transitions in the loss modulus curve were

possibly attributed to dissociation of ionic aggregates. Teyssie et al. have observed multiple

transitions in the loss modulus curve for telechelic quaternary ammonium iononomers based

on polyisoprene. They observed rubbery plateaus for their materials which decreased in

extent for longer alkyl chain substituents on the ammonium cation. For an

bis(hexadecyldimethylammonium iodide) terminated polyisoprene, two peaks in the loss

modulus curve were observed, one corresponding to the Tg of polyisoprene and one at about

35 oC, corresponding the dissociation of the ammonium ion aggregates and the end of the

rubbery plateau.993

993 Charlier, P.; Jerome, R.; Teyssie, P.; Utracki, L.A. Viscoelastic Properties of Telechelic Ionomers. 2. Quaternized α,ω-bis(dimethylamino)polyisoprene. Macromolecules 1992, 25, 617-24.

556

0.5

1.0

1.5

2.0

[ ]

Tan

Del

ta

0.1

1

10

100

[ ]

Los

s M

odul

us (M

Pa)

0.1

1

10

100

1000

10000

[ ]

Sto

rage

Mod

ulus

(MP

a)

-60 -40 -20 0 20 40 60 80Temperature ( C) Universal V3.9A TA Instruments

Figure 14.6. DMA analysis of 30 mol% phosphonium copolymer.

557

A uracil functionalized phosphonium salt was synthesized in a single step from

6-chloromethyluracil and trioctylphosphine. The salt was soluble in chloroform, a common

solvent utilized to study hydrogen bonding systems. The uracil phosphonium salt was

blended with the complementary 2.0 mol% adenine containing random copolymer at a 1:1

adenine to uracil molar ratio in chloroform solution. The blend appeared slightly cloudy,

suggesting possible phase separation of the uracil phosphonium salt. The blend was

characterized using differential scanning calorimetry, which allowed comparisons to the 2.0

mol% phosphonium copolymer and the pure adenine copolymer (Figure 14.7). Both of the

copolymers and the blend exhibited nearly identical Tg values near -50 oC. The blend of the

uracil phosphonium salt with the adenine copolymer exhibited a small melting endotherm

near 160 oC, which was characteristic of the crystalline uracil phosphonium salt. However,

upon integration of this endotherm and calculating based on the composition of the blend, it

was determined that only 30% of the uracil phosphonium salt was in the crystalline state.

This suggests that 70% of the uracil phosphonium was dissolved into the adenine-functional

random copolymer.

558

Figure 14.7. DSC analysis of blends of adenine- and phosphonium-functional random

copolymers and blend of adenine copolymer with uracil phosphonium salt.

559

Constant frequency (1 Hz), variable temperature rheological studies were conducted on

the blend of the adenine copolymer with the uracil phosphonium salt, and the individual

adenine and phosphonium functional copolymers were also run as references. The viscosity

of the adenine functionalized copolymer was the lowest out of the three polymers. The

covalently bound phosphonium copolymer possessed melt viscosity values at 25 oC that were

2.7 times higher than the adenine copolymer. The increased melt viscosities observed for

the covalent phosphonium copolymer could be attributed to either higher molecular weight, if

the SEC data are reliable, or ionic interactions between polymer chains. The blend of the

uracil phosphonium salt with the adenine copolymer produced melt viscosities that were

nearly identical to the phosphonium copolymer, across the range of temperatures studied

(25-100 oC). This suggested strong attachment of the phosphonium salt to the adenine

copolymer, without significant disruption of hydrogen bonding interactions over the range of

temperatures studied. The presence of dispersed crystals of the uracil phosphonium salt were

not expected to result in the ~3 fold increased viscosity of the blend compared to the pure

adenine functional polymer. This is due to calculations that reveal that only 2.3 wt% of the

blend consists of phase separated uracil phosphonium salt, based on DSC results, and work

from others shows negligible viscosity effects for particle dispersions at this low loading.994

The flow activation energies for each sample were similar, near 53 kJ/mol.

994 Rueb, C.J.; Zukoski, C.F. Rheology of Suspensions of Weakly Attractive Particles: Approach to Gelation. J Rheol. 1998, 42, 1451-76.

560

Figure 14.8. Rheological analysis of uracil phosphonium salt blend with adenine copolymer

and comparisons with adenine and phosphonium copolymers.

1

10

100

1000

20 40 60 80 100

Temperature (°C)

|n*|

(Pa.

s)

Adenine

A-UP+ Blend

Covalent Phosphonium

561

14.5 Conclusions

Random copolymers of a phosphonium styrene monomer and n-butyl acrylate were

synthesized in order to compare the covalent attachment of phosphonium ions to hydrogen

bonding attachment. Hydrogen bonding attachment of ionic groups was achieved through

blending of an adenine containing copolymer with a complementary uracil phosphonium salt.

Partial miscibility of the uracil phosphonium salt with the 2.0 mol% adenine-functional

copolymer was observed. Rheological studies indicated strong attachment of the uracil

phosphonium salt, with rheological behavior of the blend mirroring that of the covalent

copolymer across the range of temperatures studied. Covalent phosphonium copolymers

with higher incorporation of the phosphonium salt monomer (30 mol%) resulted in increased

Tg, a broad maximum in the small-angle X-ray scattering curve and multiple transitions

above Tg in dynamic mechanical analysis. These findings suggest ionic aggregation in the

high mole fraction phosphonium copolymer.

14.6 Future work

The next steps in this study are to examine the melt rheology of the blends at higher

temperatures to attempt to observe the dissociation of the hydrogen bonding groups and

secondly, to study phosphonium copolymers with intermediate comonomer contents, to

determine the lower limit of phosphonium comonomer resulting in ionic aggregation.



562



563

Chapter 15. Overall Conclusions

Non-covalent interactions including nucleobase hydrogen bonding and ionic

aggregation were studied in block and end-functional polymers synthesized via living

polymerization techniques such as nitroxide mediated polymerization and anionic

polymerization. Non-covalent interactions were expected to increase the effective

molecular weight of the polymeric precursors through intermolecular associations. The

influence of non-covalent association on the structure/property relationships of these

materials were studied in terms of physical properties (tensile, DMA, rheology) as well as

morphological studies (AFM, SAXS).

Terminal nucleobase functionality was studied in the form of uracil end-functionalized

homopolymers of n-butyl acrylate synthesized through nitroxide mediated polymerization

from novel functional initiators. Hydrogen bonding interactions were observed through

increased melt rheology compared to non-functional analogs.

Nucleobase functionalized block copolymers, which consisted of microphase separated

domains of nucleobase-functionalized blocks dispersed in a rubbery n-butyl acrylate matrix

exhibited enhanced hydrogen bonding interactions due to the synergy of hydrogen bonding

with microphase separation. Hydrogen bonding interactions were observed for blends of the

complementary nucleobase-functionalized block copolymers in terms of increased specific

solution viscosity as well as higher scaling exponents for viscosity with solution

concentration. In the solid state, the blends exhibited evidence of a complementary A-T

hard phase, which formed upon annealing, and dynamic mechanical analysis (DMA) revealed

564

higher softening temperatures.

Multiple hydrogen bonding interactions were utilized to reversibly attach

uracil-functional quaternary phosphonium ionic guests to complementary

adenine-functionalized triblock copolymers. The optically clear, compatible blends exhibited

ower solution viscosity and lower softening temperatures, which were ascribed to screening

of interchain hydrogen bonding interactions from the ionic guest molecules. A morphological

transition from cylinders to lamellae was also observed due to selective uptake of the uracil

phosphonium salt into the adenine containing hard domains and the resultant increased hard

phase volume fraction. The molecular recognition between a water-soluble uracil

functionalized phosphonium salt and an adenine-containing block copolymer surface was

observed using quartz crystal microbalance with dissipation (QCM-D) measurements

Covalently attached ionic groups were studied in terms of sulfonated block copolymers

synthesized via anionic polymerization. As for hydrogen bonding block copolymers, only low

block molecular weights of the sulfonated blocks (1K) were necessary to achieve microphase

separation. Strong ionic interactions resulted in greater extents for the rubbery plateau in

DMA analysis.

In contrast to the physical networks consisting of sulfonated or hydrogen bonding block

copolymers, covalent networks were synthesized using carbon-Michael addition chemistry of

acetoacetate functionalized telechelic oligomers to diacrylate Michael acceptors. The

thermomechanical properties of the networks based on poly(propylene glycol) oligomers

were analyzed with respect to the molecular weight between crosslink points (Mc) and the

critical molecular weight for entanglement (Me). A novel acid-cleavable diacrylate

565

crosslinker was synthesized and utilized as a difunctional Michael acceptor in the synthesis of

acid-cleavable crosslinked networks via Michael addition of telechelic poly(ethylene glycol)

bis(acetoacetate).

566

VITAE

Brian Douglas Mather was born in Albuquerque, New Mexico, to Joseph Douglas Mather

and Joan Cecile Voute. He was raised in New Mexico, Texas, California and Washington

State, prior to returning to Albuquerque, New Mexico at age 16. He graduated from La Cueva

High School in May 1998. He attended college at the University of New Mexico (UNM) and

obtained his Bachelor’s degree in Chemical Engineering in May 2002, graduating summa

cum laude. Brian was involved with the engineering honor society Tau Beta Pi at UNM and

won the Breece award and Donald F. Othmer awards for academic achievement. During

college, Brian interned with Sandia National Laboratories working for Dr. Douglas Loy and

Dr. Christopher Cornelius and conducted undergraduate research with Prof. James A. Brozik

in the Department of Chemistry at UNM. It was during a summer internship at Virginia Tech

in 2000, in which Brian worked for Prof. Timothy E. Long that he developed a strong interest

in polymer research. The internship attracted Brian to return to graduate school at Virginia

Tech where he worked for Prof. Timothy E. Long. Brian was a Cunningham Fellow at

Virginia Tech and also won the Chevron-Phillips Chemical Professional Excellence Travel

Award. Brian was fortunate to intern at Kraton Polymers in Houston, TX during the

summer of 2004, where he worked with Dr. Carl L. Willis. Brian met his wife, Qian Zhang

in the Chemistry Department of Virginia Tech in October 2003. Brian and Qian were

married on January 5, 2005 in Albuquerque, New Mexico. After graduating in May 2007, he

and his wife will begin work at Hewlett-Packard in San Diego, California.

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